Evaluation of Vitamin B12 Monitoring in a Veteran Population on Long-Term, High-Dose Metformin Therapy

ObjectiveVitamin B12 deficiency resulting from metformin use has been demonstrated in multiple studies. In this study, we aimed to evaluate the prevalence of vitamin B12 deficiency in patients with chronic metformin use and the relationship between vitamin B12 deficiency and diabetic neuropathy.MethodsA cross-sectional study was conducted with 162 patients. Vitamin B12 levels were measured by chemiluminescence immunoassay. Diabetic neuropathy was evaluated by patient record, nerve conduction and Michigan test for the diagnosis of diabetic neuropathy. Additional data, including demographic characteristics were collected. A linear regression model was used to evaluate variables that correlated with vitamin B12 levels and diabetic neuropathy.ResultsLow vitamin B12 levels were found in 7.3% (95% CI: 4.0–12%) of patients. In those with diabetic neuropathy, altered (low and borderline) vitamin B12 level was 64% (95% CI: 47–78%) compared to 17% (95% CI: 10–26%) in patients without diabetic neuropathy (coefficient: −110.8; CI 95%: −165.8, −59.7). Those taking a higher metformin dose had lower levels of vitamin B12 (coefficient: −0.061; CI 95%: −0.09, −0.024). In addition, female patients had higher levels of vitamin B12 compared to men (coefficient: 49.1; CI 95%: 2.3–95).ConclusionsVitamin B12 deficiency is highly prevalent, especially in patients with diabetic neuropathy. In this study an inverse correlation was found between diabetic neuropathy and the plasma level of vitamin B12. Higher doses of metformin and male sex were factors related to lower levels of vitamin B12.

Background: Metformin, a key therapy for T2DM in Sub-Saharan Africa (SSA) where T2DM is prevalent has been linked to VitB12 deficiency mainly due to malabsorption.Objectives: To determine the prevalence of and risk factors for metformin-associated vitamin B12 deficiency in patients with T2DM in SSA and to provide an overview of the available guidelines on screening and treatment of vitamin B12 deficiency associated with metformin therapy.Methods: Literature search: PubMed, MEDLINE, SCOPUS, AJOL, EMBASE and Cochrane Library databases were searched for relevant articles between January 2002 and December 2022. Additional articles were searched in Grey literature as well as manual searches in reference lists and citations. Clinical practice guidelines on diabetes management from SSA region were searched using key search words.Inclusion criteria: Studies assessing effects of metformin on vitamin B12 in patients with T2DM in countries in SSA and all available clinical practice guidelines on diabetes management from SSA.Exclusion criteria: Studies with insufficient data, review articles and non-English articles or guidelines.Data extraction and synthesis: From articles: Relevant data including publication information, study characteristics, intervention details and outcome measures. Quality assessment of the articles was performed using the Center for Evidence-Based Management (CEBMa) (2014) Tool from guidelines: Relevant data including screening, diagnosis, and monitoring vitamin-B12 status and treatment of vitamin B12 deficiency.Results: Article selection: Initial search yielded 24 articles. After screening titles and abstracts, 13 articles were eligible for full-text review but only seven met the inclusion criteria. All were cross-sectional studies except one case-control study.Guidelines selection: Twenty-two guidelines from 18 countries were retrieved.Key findings: N=1075 . Prevalence: 5-41%.Risk factors: High metformin dose, long durationof metformin therapy and diabetes, advanced age, high BMI and body weight, better glycaemic control, non-black ethnicityGuidelines: Few, non-evidence-based, nonrecommending routine screening and treatment.Conclusions: The prevalence of vitamin B12 deficiency amongst metformin-treated T2DM in SSA varied considerably. The risk factors identified included; high dose metformin, a longer duration of metformin and diabetes, non-black ethnicity and a good glycaemic control. Guidelines for the screening, monitoring and treatment of vitamin B12 associated with metformin therapy are generally lacking in SSA and were not evidence-based. Recommendations: Selective screening in high-risk symptomatic individuals with T2DM on metformin therapy. There is a need to conduct randomized clinical trials in SSA for evidencebased guidelines development.

Metformin is a cornerstone medication in the management of type 2 diabetes. Metformin is safe, effective, and inexpensive; however, it is associated with vitamin B12 deficiency. This study set out to evaluate the rate of vitamin B12 deficiency in Vietnamese patients with type 2 diabetes who were treated with metformin and to investigate factors associated with vitamin B12 deficiency. This is a cross-sectional study that was conducted in Vinmec Central Park Hospital from February to June 2023. The clinical and paraclinical characteristics of the participants were recorded, and the levels of vitamin B12 and folate were measured. The rate of vitamin B12 deficiency in patients treated with metformin was found to be 18.6%. Further, the duration of diabetes, duration of metformin use, metformin dose, and hemoglobin levels were statistically associated with vitamin B12 deficiency with OR (95% CI) = 1.12 (1.03-1.19), 1.01 (1.00-1.02), 1.002 (1.001-1.002), 0.74 (0.55-0.99), respectively. After adjusting for covariates, a metformin dose greater than the median dose remained the only parameter associated with vitamin B12 deficiency, with OR (95% CI) = 4.10 (1.62-10.36). Moreover, when combining both long-term use of metformin and a metformin dose greater than the median dose, the OR increased to 5.25 (95% CI: 2.11-13.15). These results demonstrate that vitamin B12 deficiency in patients treated with metformin is quite prevalent in Vietnam and that those with long-term use of metformin (48 months or more) and high metformin dose (1000 mg/day or more) are at high risk of experiencing this adverse effect and so require screening.

Background/Purpose: Type 2 diabetes mellitus (T2DM) is a worldwide pathology with several complications, and 50% of patients with T2DM develop peripheral neuropathy (PN) in the long term. The present study aimed to review the literature on the association between PN and vitamin B12 deficiency in patients with T2DM treated with metformin. Materials and methods: A literature review was carried out in the PubMed Central, Cochrane, Scielo, Scopus and Embase databases, from 2015 to 2021. We found 755 studies, of which 16 were included. Results: The serum level of vitamin B12 was lower in individuals with at least one neurological symptom. Treatment with metformin was associated with reduced serum vitamin B12 levels, and its use was defined as a probable cause of PN due to reduced vitamin B12. Studies that performed supplementation with methylcobalamin demonstrated significant improvement in neuropathic symptoms. Vitamin B12 supplementation therapy for diabetic patients undergoing metformin treatment has been suggested. Conclusion: Deficiency of vitamin B12 associated to metformin can be considered a risk factor for PN. Periodically evaluation of serum levels of vitamin B12 is recommended for patients on metformin treatment.

<h3>Introduction</h3> Vitamin B12 deficiency is a recognised problem in patients after surgery for OG cancer owing to the implications of surgery on gastric acid and intrinsic factor (IF) production (which are needed for Vitamin B12 metabolism). However it is postulated that for some patients with OG cancer their deficiency predates surgery. This study investigates the prevalence of preoperative Vitamin B12 deficiency in patients with OG cancer. <h3>Method</h3> A retrospective observational study was undertaken of patients who had surgery for OG cancer between January–December 2014. Active Vitamin B12 levels considered ‘borderline deficiency’ are sent for Methylmalonic acid (MMA) analysis. MMA levels above the normal range for age indicate deficiency. Weight loss data was also collected. <h3>Results</h3> Active Vitamin B12 ±MMA levels were available for 89 patients. 16% of patients had a proven Vitamin B12 deficiency. 27% of patients with Gastric Adenocarcinoma (AC) had a deficiency. Table 1Demographics, prevalence of Vitamin B12 deficiency and weight loss in the study: <h3>Conclusion</h3> OG cancer most commonly affects people &gt;65 years of age. The prevalence of Vitamin B12 deficiency increases with age. This is attributed to a reduction in stomach acid and pepsin production. However the study population has a higher prevalence of Vitamin B12 deficiency than the general population (65–74 years age 1 in 6 vs 1 in 20).¹Implications of deficiency include anaemia, which can have significant consequences for surgery, but also symptoms such as fatigue; depression; problems with memory and understanding; all of which can negatively impact on patients’ Quality of Life. Deficiency can be masked as symptoms which may be attributed to the cancer and/or its treatment. Older age, weight loss and poor nutrition can contribute to Vitamin B12 deficiency in these patients with OG cancer. However 1/5 of the deficient subgroup had stable/gained weight suggesting other possible causes of deficiency such as the use of antacid medication. The high prevalence of Vitamin B12 deficiency in patients with Gastric AC maybe related to the possible presence of gastritis, leading to malabsorption of Vitamin B12, and undiagnosed Pernicious Anaemia; both of which are risk factors for Gastric cancer. Assessment of Vitamin B12 preoperatively is therefore an important component of nutritional assessment in OG cancer. <h3>Disclosure of interest</h3> None Declared. <h3>Reference</h3> Clarke, <i>et al</i>. Vitamin B12 and folate deficiency in later life. Age Ageing 2004;33:34–41

Vitamin B12 Deficiency Among the many causes of organic psychoses are a number of processes which may be cured or arrested by the right treatment and by early recognition. This includes deficiency of vitamin B12. There is, therefore, a temptation to carry out sophisticated tests for vitamin B12 deficiency in all psychiatric patients. However, until cheaper and fully-automated techniques become available, routine vitamin B12 assays cannot be justified in psychiatric patients. At the present time a hemoglobin estimation and a careful inspection of the peripheral blood film by an experienced hematologist appear to be the most economic primary screening test for vitamin B12 deficiency. Nevertheless, psychiatrists should be alert to the possibility of vitamin B12 deficiency in patients with unexplained fatigue and in those with confusional states or dementia of unknown origin. Another presentation may be impotence which sometimes precedes other neurological manifestations of the disease. Even in patients who are not anemic or have no blood film abnormalities (which is uncommon) the possibility of missing cases of hypovitamin B12 deficiency can be further diminished by doing serum B12 assays in patients who are clinically at risk. For example, this includes post-gastrectomy patients, those with a familial history of pernicious anemia and those with an associated auto-immune disorder, such as thyroid disease. Folic Acid Deficiency The available evidence linking folate deficiency with psychiatric disorders is inconclusive. It is probable that the observed excess of folic acid deficiency in psychiatric patients can be explained on the basis of malnutrition, chronic physical illness, alcoholism or other drug usage. An important exception is brain damage and mental retardation in infants with inborn errors of folic acid metabolism. Further evaluation of folate deficiency is indicated, particularly in the affective disorders and in ambulatory, non-institutionalized, epileptic patients receiving anticonvulsant medication.

Multiple studies have established a higher prevalence of vitamin B12 deficiency in patients who have type 2 diabetes mellitus (T2DM). Metformin is prescribed as the 1st line oral glucose-lowering medication for individuals with T2DM. However, metformin therapy has been linked to vitamin B12 malabsorption, which can result in both biochemical and clinical manifestations of vitamin B12 deficiency. The long-term use of metformin is associated with a significant decrease in vitamin B12 levels, particularly in doses greater than 2000 mg per day over a period of 4 years. Vitamin B12 is a water-soluble vitamin. It acts as a cofactor for enzymes involved in DNA synthesis and neuroprotection at the cellular level. Hence, vitamin B12 deficiency can lead to various clinical consequences, including hematologic abnormalities such as megaloblastic anemia and hypersegmented neutrophil formation, peripheral neuropathy, and progressive axonal demyelination, hyperhomocysteinemia (HHcy). The latest "standards of medical care in diabetes-2017" issued by the American diabetes association recommends periodic assessment of B12 status and, if necessary, the use of B12 replacement therapy in diabetic patients taking metformin. In order to address the vitamin B12 deficiency associated with metformin several therapies are available including prophylactic supplements of calcium and vitamin B12, discontinuation of metformin, and replenishment of vitamin B12 stores through intramuscular or oral therapy. It is important to regularly monitor vitamin B12 levels for at least annually to prevent complications of vitamin B12 deficiency and continue with supplementation if metformin is still being used.

Background: Vitamin B12 deficiency can cause peripheral neuropathy. Metformin use is associated with vitamin B12 deficiency. Objective: To define the prevalence of vitamin B12 deficiency in patients with type 2 diabetes mellitus (T2DM) and its possible relation to metformin therapy. Patients and Methods: A crosssectional study of T2DM patients on chronic metformin therapy was conducted at Benghazi Diabetic Center during 2011. Demographic data, type, and duration of treatment reported adherence, and vitamin B treatment were all documented. History and examination for evidence of peripheral neuropathy were recorded. Serum vitamin B12 levels were measured (reference value 159-1000 pg/ml). Results: 500 patients were included of whom 175 were males (35%). Mean (SD) age was 58.6 ± 9.9 years and duration of diabetes 13.6 ± 8.4 years. Of these 358 (71.8%) were on insulin and metformin' 93 (18.6%) on sulphonylureas and metformin, 26 (5.2%) were on insulin and sulphonylurea and metformin triple monotherapy. Mean serum B12 level for all patients was 439 ± 212 pg/ml with males having significantly higher levels than females (512 ± 226 vs. 399± 193; p=0.001). Vitamin B12 levels were &lt;159 pg/ml in 2%, &lt;200 p g/ml in 7.4%, and &lt;300 pg/ml in 30.8% of the patients. There was no significant difference in the B12 levels among patients who were adherent to metformin therapy and those who were not (432 ± 206 vs. 448 ± 219 pg/ml; p=0.4). Serum B12 levels were not different in the patient with history and/or examination suggestive of neuropathy and patients who have any (443 ± 216 vs. 423 ± 204; p=0.5. Conclusions: The prevalence of vitamin B12 deficiency in diabetic patients attending Benghazi diabetic center was dependent on the cut off points used. This is comparable with previous studies. No clear relationship was evident with metformin therapy nor with neuropathy.

Long-term and high-dose treatment with metformin is known to be associated with vitamin B12 deficiency in patients with type 2 diabetes. We investigated whether the prevalence of B12 deficiency was different in patients treated with different combination of hypoglycemic agents with metformin during the same time period. A total of 394 patients with type 2 diabetes treated with metformin and sulfonylurea (S+M group, n = 299) or metformin and insulin (I+M group, n = 95) were consecutively recruited. The vitamin B12 and folate levels were quantified using the chemiluminescent enzyme immunoassay. Vitamin B12 deficiency was defined as vitamin B12≤300 pg/mL without folate deficiency (folate>4 ng/mL). The mean age of and duration of diabetes in the subjects were 59.4±10.5 years and 12.2±6.7 years, respectively. The mean vitamin B12 level of the total population was 638.0±279.6 pg/mL. The mean serum B12 levels were significantly lower in the S+M group compared with the I+M group (600.0±266.5 vs. 757.7±287.6 pg/mL, P<0.001). The prevalence of vitamin B12 deficiency in the metformin-treated patients was significantly higher in the S+M group compared with the I+M group (17.4% vs. 4.2%, P = 0.001). After adjustment for various factors, such as age, sex, diabetic duration, duration or daily dose of metformin, diabetic complications, and presence of anemia, sulfonylurea use was a significant independent risk factor for B12 deficiency (OR = 4.74, 95% CI 1.41–15.99, P = 0.012). In conclusion, our study demonstrated that patients with type 2 diabetes who were treated with metformin combined with sulfonylurea require clinical attention for vitamin B12 deficiency and regular monitoring of their vitamin B12 levels.

BackgroundMetformin is frequently prescribed as a first-line oral hypoglycemic drug to treat insulin resistance-causing type 2 diabetes mellitus (T2DM). Long-term metformin use results in vitamin B12 deficiency, which is frequently overlooked and undiagnosed. A severe deficit may cause severe anemia and gastrointestinal, or neurological issues. Studies are scarce on this issue in Pakistani patients with T2DM.The current study aimed to estimate the prevalence of metformin-induced vitamin B12 deficiency in T2DM patients and to explore how it relates to metformin dosage or duration of therapy.MethodologyA descriptive cross-sectional study was conducted on 260 T2DM patients using metformin therapy for more than a year and attending the outpatient diabetes clinic and the medicine department of Sheikh Zayed Hospital, Rahim Yar Khan, Pakistan, from August 2022 to October 2023. All socio-demographic, clinical, and general characteristics were collected. Blood samples were taken to measure the serum vitamin B12 levels, and based on these levels, deficient and normal group characteristics were compared. Statistical analysis was performed using IBM SPSS Statistics for Windows, Version 23 (Released 2015; IBM Corp., Armonk, New York, United States).ResultsBased on the serum levels of vitamin B12 of the studied T2DM on the metformin regimen, the overall prevalence of vitamin B12 deficiency was found to be 36.54% (95). The B12 deficiency was higher among the age group of 41-50 years (109, 41.9%), female gender (150, 57.7%, p-value=0.0035), urban residents (194, 74.6%), non-smokers (197, 75.8%), and with a history of chronic disease (131, 50.4%). There was a statistically significant difference in vitamin B12 levels based on T2DM duration (p=0.012), with a higher prevalence in patients with a longer diabetes history of more than two years. There was no discernible statistical relationship between patients receiving different dosages of metformin (odds ratio (OR)=0.8627; 95% confidence interval (CI) (0.5195, 1.4326); p-value=0.568), durations of metformin (OR=0.7400; 95% CI (0.442, 1.2325); p-value=0.247), or intake of vitamin B12 (OR=0.8532; 95% CI (0.5073, 1.4351); p-value=0.549).ConclusionThe prevalence of vitamin B12 deficiency impacted more than one-third of T2DM patients using metformin (36.54%). The risk of vitamin B12 deficiency may increase in females with higher metformin dosages and longer durations of treatment. Furthermore, a statistically significant correlation exists between vitamin B12 deficiency and the longer duration of T2DM.These findings highlight the relevance of routinely monitoring serum levels of vitamin B12 among those with T2DM, especially when metformin is being given for over a year or at doses greater than 1000 mg per day. These preventive strategies will aid in the early detection of vitamin B12 deficiency, allowing patients to be treated with supplementation before problems such as anemia or neuropathies arise, resulting in improved quality of life and a lower socioeconomic burden.

Vitamin B12 Deficiency in Patients with Chronic Myeloid Leukemia

Globally, type 2 diabetes mellitus (T2DM) is a common metabolic disorder affecting millions of people annually. Metformin, a prevalent prescribed antihyperglycemic medication for T2DM, has been associated with vitamin B12 deficiency. This study aimed to determine the prevalence of vitamin B12 deficiency in T2DM patients receiving metformin. This retrospective record review study was based on T2DM patients receiving metformin at a single tertiary healthcare center. The prevalence of vitamin B12 deficiency is defined as a serum level <145 pmol/L. Statistical analysis assessed the association between vitamin B12 deficiency and metformin usage. A total of 246 T2DM patients were included in the study. Among patients who used metformin, 7.7% were found to have vitamin B12 deficiency compared to 4.8% among those who did not use metformin, while the difference was not statistically significant (p=0.571). However, the median (IQR) level of vitamin B12 among metformin users (296 (186)) was significantly lower than that among patients who do not use metformin (382 (370)), p=0.001. The study's findings shed light on the important role of routine screening of vitamin B12 levels in patients on metformin, especially those on long-term use, for early identification and management of deficiency, leading to improved patient outcomes. Our study revealed a significantly lower level of vitamin B12 among metformin users in T2DM patients. However, the prevalence of vitamin B12 deficiency among metformin users did not differ significantly from those who do not use metformin.

IntroductionPatients with Crohn’s Disease (CD) who frequently have ileal involvement are at increased risk of vitamin B12 deficiency. Vitamin B12 deficiency in patients with ulcerative colitis (UC) is not widely...

Background/Objectives: Vitamin B12 deficiency is a common but often underdiagnosed complication in patients with type 2 diabetes (T2D) undergoing long-term metformin therapy. Accurate early prediction could enable targeted screening and timely intervention. This study aimed to develop and interpret a machine learning model for predicting vitamin B12 deficiency in metformin-treated patients with T2D, using eXtreme Gradient Boosting (XGBoost). Methods: A retrospective cross-sectional study was conducted at a single endocrinology centre (La Rabta University Hospital, Tunis, Tunisia). Patients with T2D treated with metformin for at least three years were included (n = 257); those with conditions independently affecting vitamin B12 metabolism were excluded. Vitamin B12 deficiency was defined as a serum B12 level below 150 pmol/L or a borderline level (150-221 pmol/L) with concurrent hyperhomocysteinemia (>15 μmol/L). XGBoost was selected after comparison with Logistic Regression (L2), Random Forest, and Support Vector Machine on the same 5-fold stratified cross-validated pipeline. Hyperparameters were optimized via Bayesian search (100 iterations × 5-fold stratified cross-validation), with the Matthews correlation coefficient (MCC) as the primary optimization metric to account for class imbalance. Model interpretability was achieved using SHapley Additive exPlanations (SHAP). Discrimination and calibration were assessed on an independent test set using bootstrap 95% confidence intervals (2000 resamples). Results: Of 257 patients, 95 (37.0%) presented with vitamin B12 deficiency. On the independent test set (n = 52), the optimized XGBoost model achieved an ROC-AUC of 0.671 [95% CI: 0.514-0.818], sensitivity of 0.737 [95% CI: 0.533-0.938], specificity of 0.545 [95% CI: 0.375-0.710], MCC of 0.273 [95% CI: 0.018-0.517], and a Brier Score of 0.259. SHAP analysis identified HbA1c, microalbuminuria, autonomic neuropathy, BMI, DN4 score, and fasting glucose as the most influential predictors. Nonlinear SHAP interaction plots revealed an increased predicted risk in patients with low HbA1c combined with a high cumulative metformin dose. Conclusions: The XGBoost-SHAP framework provided interpretable predictions of vitamin B12 deficiency in patients with T2D on metformin, identifying key clinical profiles for targeted screening. External multi-centre validation is required before clinical deployment.

Vitamin B₁₂ Deficiency Masquerading as Clozapine-Resistant Psychotic Symptoms in Schizophrenia