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Long term treatment with meformin in patients with type 2 diabetes and risk of vitamin B12 deficiency: randomized placebo controlled trial
... 1 The prevalence of vitamin B12 deficiency in diabetes mellitus (DM) ranges between 5.8% and 52%. [2][3][4][5][6][7][8] The association of vitamin B12 deficiency and Type 2 diabetes (T2DM) is mainly due to metformin's long-term use, as demonstrated by evidence from both observational and interventional studies. 1,8 This association's exact mechanism is unknown but has been ascribed to intestinal malabsorption of vitamin B12 due to metformin. ...
... 22 The variation in the cut-off values for vitamin B12 deficiency across studies may also explain the wide variations in B12 deficiency from 5.8% to 52% in studies worldwide. 5,6,8,10,19,20,[23][24][25] In some studies, individuals with borderline vitamin B12 levels were further screened for evidence of elevated serum methylmalonic acid or homocysteine concentrations. 2 In this way, patients with borderline vitamin B12 levels were further categorised into those with or without vitamin B12 deficiency. ...
... 19,28 Levels of serum B12 are inversely associated with the dose and duration of metformin use. 5,10,[28][29][30][31] Reports have shown a decrease in vitamin B12 levels as early as four months after initiation of metformin. 10,31 The exact mechanism of this association is unknown but is ascribed to the binding of the hydrophobic tail of biguanide to the hydrocarbon core of membranes. ...
Objective
To estimate the prevalence of Vitamin B12 deficiency among patients with diabetes.
Methodology
This cross-sectional study was undertaken on 351 patients with diabetes at a specialised public diabetes clinic in Gaborone between July 2017 and October 2017. Clinical, anthropometry and laboratory data were collected. Vitamin B12 deficiency was defined by levels < 150 pmol/l.
Results
The mean (SD) age of the participants was 57 (15) years, two-thirds (67.2%) were females, and the majority (92.9%) had Type 2 diabetes. Most (89.5%) participants were on metformin. The prevalence of vitamin B12 deficiency was 6.6%. Compared with participants with normal Vitamin B12 levels, deficient participants were significantly older (64 vs. 56 years, p = 0.014) and had a longer duration of metformin use (7 vs. 4 years, p = 0.024). The use of acid blockers was also associated with vitamin B12 deficiency (p = 0.012). There was no difference in the prevalence of peripheral neuropathy between those with normal and deficient vitamin B12 levels.
Conclusion
Vitamin B12 deficiency exists among patients with diabetes in the setting discussed. Regular vitamin B12 assessment may be beneficial, especially among diabetes patients who are old, those taking metformin over a long duration and patients on acid blockers.
... In view of the minimum daily requirement, about 3-6 years would be required for a normal healthy individual to be deficient in cobalamin if its absorption was to cease abruptly and completely. 18,23 The preliminary steps in the metabolism of vitamin B 12 involve its release from animal sources, a process mediated by the action of pepsin and gastric acid. Following its release, it then binds to R-protein secreted by the salivary glands. ...
... Vitamin B 12 exists in two metabolically active forms as methyl cobalamin and adenosyl cobalamin. 23,25 Vitamin B 12 acts as a cofactor for methionine synthase in the methylation of homocysteine to methionine, which is later activated to s-adenosyl-methionine that donates its methyl group to methyl acceptors such as myelin, neurotransmitters and phospholipids. Metabolically significant vitamin B 12 deficiency thus will result in disruption of the methylation process and the accumulation of intracellular and serum homocysteine. ...
... The accumulation of MMA has been implicated in impaired neuronal membrane fatty acid synthesis as a result of production of long-chain fatty acids with odd number carbon atoms, as against an even number carbon atoms in the presence of methyl malonyl CoA. 22,23 Vitamin B 12 is also essential for the synthesis of hormones such as melatonin and epinephrine, as well as the monoaminergic neurotransmitters such as serotonin, norepinephrine and dopamine. 26,27 Thus, these processes are thought to be responsible for the resultant neurocognitive and neuropsychiatric manifestations accompanying vitamin B 12 deficiency. ...
Background
The potential effect of chronic metformin pharmacotherapy to cause vitamin B 12 deficiency has been of tremendous concern especially among diabetic patients. Haematological abnormalities following vitamin B 12 deficiency among diabetic patients contribute immensely to morbidity and mortality in this group of patients.
Aim
This study was designed to elucidate the chronic haemato-toxicologic adverse profile for metformin with respect to its potential to induce vitamin B 12 deficiency via reduction in the gastrointestinal absorption of vitamin B 12 by performing comparative analyses between the serum vitamin B 12 levels and haematological indices among metformin-treated and metformin-naive type 2 diabetes mellitus (DM) patients attending the outpatient Endocrinology Clinic of Irrua Specialist Teaching Hospital (ISTH), Irrua, Edo State, Nigeria, with the rational purpose of alleviating the associated morbidity and mortality.
Materials and Methods
This was a case–control, prospective, analytical, and observational study of 200 adult participants (100 per group) attending the Endocrinology Outpatients Clinic of ISTH. Serum vitamin B 12 levels were analysed using an immunoassay technique. Haematological indices were determined using standard methods, and patients examined for clinical features of anaemia. Data were presented using tables and charts. χ ² and t-tests were used to compare discrete and continuous data, respectively. The receiver operating characteristic (ROC) curve was plotted graphically to determine the sensitivity and specificity of using serum vitamin B 12 assay as a screening and diagnostic test for the haematologic abnormality of ovalocytosis among the metformin-treated type 2 DM patients.
Results
A total of 200 type 2 diabetic patients comprising 100 metformin-treated and 100 metformin-naive patients with average age of 55.8 ± 9.3 years were studied. The mean serum vitamin B 12 levels in metformin-treated and metformin-naive participants with frank vitamin B 12 deficiency (i.e. mean serum vitamin B 12 level ≤ 199 pg ml ⁻¹ ) were 158.29 ± 29.27 pg ml ⁻¹ and 173.95 ± 14.21 pg ml ⁻¹ , respectively ( p = 0.028). This was significantly lower for the metformin-treated group compared to metformin-naive group with respect to the participants with frank vitamin B 12 deficiency. There were instances of statistically significant differences between the mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and total white blood cell (WBC) count among the metformin-treated compared to the metformin-naive type 2 DM patients. The ROC curve showed that serum vitamin B 12 assay had moderate sensitivity of 72% with moderate specificity of 66% at detecting the presence and absence of ovalocytosis in the presence and absence of frank vitamin B 12 deficiency, respectively, among the metformin-treated group (i.e. serum vitamin B 12 ≤ 199 pg ml ⁻¹ with p = 0.002).
Conclusion
The occurrence of vitamin B 12 deficiency was high among metformin-treated type 2 DM patients. Our study showed remarkable statistically and clinically significant differences in the chronic haemato-toxicology of metformin on mean serum vitamin B 12 level, ovalocytosis, MCV, MCH and total WBC count between the metformin-treated and metformin-naive participants. We advocate for vitamin B 12 supplements in this group of patients via the parenteral route of administration, most preferably the intramuscular site injection; in order to prevent the occurrence of vitamin B 12 deficiency among them. Lastly, we recommend the use of serum vitamin B 12 assay and complete blood count (CBC) with peripheral blood films (PBFs) as a reliable way to diagnose and screen for vitamin B 12 deficiency among metformin-treated type 2 DM patients.
... Most current clinical recommendations suggest that, in the absence of contraindications, metformin should be the first-line medication for the treatment of type 2 diabetes mellitus (T2DM) [2,3]. Most of the side effects of metformin are mild, transient or clinically difficult to detect, such as B12 deficiency signs [4][5][6][7][8][9]. ...
... In this group of patients with long-term T2DM and good metabolic control, we observed a prevalence of 14% of vitamin B12 deficiency exclusively among metformin users. Previous studies have shown a prevalence of vitamin B12 deficiency of 10-30% among users of metformin and 4-7% among non-metformin users [5][6][7]9]. The high prevalence of patients using met- formin has come to our attention. ...
... Although there was a clear association between the use of metformin and the vitamin B12 deficiency, our findings did not demonstrate clinical impact in the main consequence of this deficiency. Several authors have been able to demonstrate a decrease in the serum concentrations of cobalamin among metformin users, but neither one of them could find clinical neuropathic consequences of this vitamin deficiency [9,25,28,29]. ...
Background. The use of metformin has been associated with vitamin B12 deficiency in patients with type 2 diabetes mellitus. Objective. The present study evaluates the relationship between vitamin B12 deficiency and its risk factors. Moreover, it investigates the relationship between established deficiency and clinically detectable peripheral neuropathy. Material and methods. A cross-sectional study involving patients with type 2 diabetes mellitus who were assisted at a public health care service, which is a reference center in Diabetes. Peripheral neuropathy was detected by Neuropathy Symptom Score, Vibration Sensitivity Test, Achilles Reflex and Monofilament Test. Vitamin B12 levels were determined by means of two laboratory measurements. Results. The study included 316 subjects, from which 91% were metformin users. Vitamin B12 deficiency was observed in 14% of participants in the study. All patients with vitamin B12 deficiency used metformin, with an odds ratio of 2.6 for those using doses higher than 1000 mg/day (95% confidence interval: 1.3-5.3, p = 0.009). Vitamin B12 deficiency was also statistically related to the use of angiotensin-converting enzyme inhibitors (p = 0.02). Peripheral neuropathy was observed in 41% of patients and was not related to vitamin B12 deficiency. The prevalence of peripheral neuropathy was lower among metformin users (39% vs. 60%; p = 0.04). Conclusions. This study demonstrated a dose-dependent association between metformin use and vitamin B12 deficiency, in addition to an association with the use of angiotensin-converting enzyme inhibitors. In contrast, Vitamin B12 deficiency was not related to clinically detected neuropathy.
... Cobalamin deficiency is highly prevalent among T2DM, especially in ones who consume metformin (up to 33%) [18]. Metformin is believed to reduce cobalamin level by inhibiting its absorption. ...
... ADA recommends people taking metformin to get periodic testing of cobalamin levels particularly in those with anemia or peripheral neuropathy [6]. Unfortunately, there are no guidelines to address how often, how much, or how to administer cobalamin supplementation to T2DM patients [13,18]. Therefore, the purpose of this systematic review is to gather available data regarding the efficacy of cobalamin supplementation in T2DM patients on metformin medication especially in increasing serum cobalamin, preventing progression, and treating peripheral neuropathy. ...
Background and aims
Metformin-treated type 2 diabetes mellitus (T2DM) patients are at higher risk of vitamin B12 deficiency and more severe neuropathy symptoms. There is still no guideline suggesting vitamin B12 supplementation for this population. This study aimed to analyze the efficacy of vitamin B12 supplementation in this population.
Method
Studies reporting the efficacy of vitamin B12 supplementation in metformin-treated T2DM patients were systematically searched in PubMed, Cochrane, EBSCOHost, and Scopus following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Additional relevant studies were searched manually through citations. Study quality and risk of bias were assessed using suitable tools.
Results
Seven clinical trials with a total of 506 participants were included. Using the Cochrane's Risk of Bias 2 tools for clinical trials, 4 studies were assessed to have high risk of bias and 3 studies had low risk of bias. There were 5 studies that measured changes in serum vitamin B12 level, all of which reported a statistically significant increase after supplementation. Significant reductions in homocysteine after supplementation were found in 2 studies. Its effect on neuropathy symptoms was still unclear, with 2 studies reporting a significant improvement and 1 study reporting no significant effect.
Conclusions
The results of this systematic review support the implementation of vitamin B12 supplementation for metformin-treated T2DM to prevent or treat vitamin B12 deficiency and neuropathy. More high-quality clinical studies are required to generate quantitative analysis and to encourage supplementation in available guidelines.
... The risk of developing vitamin B12 deficiency in metformin users is related to the dose and duration of metformin use, which is the most consistent risk factor found in previous studies (16) . Which is not shown in this study because of the many reasons mentioned above. ...
... The deficiency of vitamin B12 in the serum of type II diabetes mellitus is explained as in (16) . The risk of developing metformin-associated vitamin B12 deficiency is greatly influenced by the patient's characteristics such as age, health status, metformin dose, and length of use (15) . ...
To evaluate the association of metformin use with vitamin B12 deficiency in Iraqi patients with type II diabetes mellitus. This is a prospective study conducted among the diabetic patients coming to the outpatient clinic at Al-Zahraa teaching hospital in Al-Kut and Al-Baghdad teaching hospital in the medical city of Baghdad from October to December 2018, the samples taken randomly after taking a short history from each patient. Data concerning age, medical disease including diabetes mellitus, and medications including metformin (average daily dose and duration of use) at the time of vitamin B12 measurement were collected. Our patients were classified into 2 groups: diabetic patients taking metformin, diabetic patients not taking metformin. The statistical analysis was done using the SPSS 23 statistical package to analyze the data. The two groups were
compared by Paired Samples t-test. Data are presented as the number, percentage, mean value, and standard deviation. The p-value < 0.05 was taken as significant.
... 11 Consequently, the fact that chronic metformin pharmacotherapy may raise homocysteine levels through vitamin B 12 deficiency, 12,13 particularly in the absence of exogenous supplementation of folic acid or B-group vitamins, 14,15 could worsen its associated cardiovascular, haemopoietic and neurological morbidity. Despite these above-mentioned clinical conditions associated with vitamin B 12 deficiency and its high degree of occurrence in adult individuals with diabetes, there are neither global nor national guidelines recommending the routine assessment of serum vitamin B 12 levels, especially in Nigeria, a nation with a high prevalence of nutritional deficiencies, as there are poor availability of data on the burden and predictors of vitamin B 12 deficiency in adult individuals with DM. [15][16][17] In fact, frank serum vitamin B 12 deficiency has been found to manifest with laboratory picture of haematologic abnormalities such as anaemia, macro-ovalocytosis and hypersegmented neutrophils. [17][18][19][20] Briefly, pack cell volume (PCV) is a measure of the proportion of red blood cells and haemoglobin (Hb). ...
... Despite these above-mentioned clinical conditions associated with vitamin B 12 deficiency and its high degree of occurrence in adult individuals with diabetes, there are neither global nor national guidelines recommending the routine assessment of serum vitamin B 12 levels, especially in Nigeria, a nation with a high prevalence of nutritional deficiencies, as there are poor availability of data on the burden and predictors of vitamin B 12 deficiency in adult individuals with DM. [15][16][17] In fact, frank serum vitamin B 12 deficiency has been found to manifest with laboratory picture of haematologic abnormalities such as anaemia, macro-ovalocytosis and hypersegmented neutrophils. [17][18][19][20] Briefly, pack cell volume (PCV) is a measure of the proportion of red blood cells and haemoglobin (Hb). When PCV value is low, a patient is said to be anaemic. ...
Background
Metformin-induced vitamin B 12 deficiency state or metformin-induced hypocobalaminemia is gradually becoming an epidemic among diabetic patients on moderate-to-high doses of metformin or those diabetic patients on metformin for a long period of time. The potential effect of chronic metformin pharmacotherapy to cause vitamin B 12 deficiency with abnormalities in haematologic indices and central/peripheral neuropathy has been widely reported. Long-term usage of metformin has been reported to be associated with intestinal malabsorption of vitamin B 12 culminating in vitamin B 12 deficiency with likely associated haematologic abnormalities (including macro-ovalocytic anaemia and immune dysfunctioning due to hypersegmentation of polymorphonuclear leukocytes), central/peripheral neuropathy and manifestation of biochemical derangements such as elevated homocysteine and methyl malonate levels.
Aim
This study aimed to determine the correlation between serum vitamin B 12 levels and various haematologic indices among metformin-treated type 2 diabetic patients in a clinical practice setting with the rational purpose of alleviating/preventing the associated derangements.
Materials and Methods
This was a case-control, prospective, analytical, observational study of 200 adult participants (100 per group) attending the Endocrinology Out-patients Clinic of Irrua Specialist Teaching Hospital, Irrua, Edo State, Nigeria. For each participant, serum vitamin B 12 level was determined using a vitamin B 12 immunoassay technique, while the corresponding complete blood count was done using PCE-210N autohaematology analyser. Data were presented using tables and figures. Chi-square test was used to compare categorical variables, Student t-test was used in comparing means of continuous variables, while Pearson’s correlation study was done to determine the existence of any statistically significant correlation(s) between the serum vitamin B 12 levels and various haematologic indices among the participants.
Results
Approximately 41% versus 20% of the metformin-treated and metformin-naive diabetic patients, respectively, had frank vitamin B 12 deficiency. There was a statistical difference between the total serum vitamin B 12 levels in male and female diabetic patients with p = 0.048. Also, statistically significant differences existed with respect to mean corpuscular volume (MCV), mean corpuscular haemoglobin and total white blood cells count among the metformin-treated and metformin-naive diabetic patients. Furthermore, a statistically significant weak positive correlation existed between pack cell volume (PCV) and serum vitamin B 12 level ( r = +0.148, p = 0.037), but a statistically significant weak negative correlation existed between MCV and serum vitamin B 12 level ( r = −0.245, p = 0.0001). In addition, the test for associations between the serum vitamin B 12 categorization status or metformin exposure status and the peripheral neuropathy components assessment revealed that there were statistically significant associations between the serum vitamin B 12 categorization status or metformin exposure status versus pain sense ( p < 0.0001 or <0.001), vibration sense ( p < 0.0001 or <0.001) and light touch sense ( p < 0.0001 or <0.001) among the participants.
Conclusion
In this study, statistically significant weak positive and weak negative correlations existed between serum vitamin B 12 level versus PCV, and serum vitamin B 12 level versus MCV, respectively. The peripheral neuropathy components assessment revealed that there were statistically significant associations between the serum vitamin B 12 categorization status or metformin exposure status versus pain sense, vibration sense and light touch sense among the participants.
... 6 The main cause of this deficiency is the use of metformin as the first-line pharmacological treatment for T2DM in clinical practice. 7 Accumulating evidence [8][9][10][11][12] suggests that long-term use of metformin lowers serum vitamin B 12 levels. Furthermore, bariatric surgery, which is commonly used with obese patients with T2DM, is also a risk factor for malabsorption of vitamin B 12 . ...
... 7 Accumulating evidence, however, has confirmed that its long-term use contributes to vitamin B 12 deficiency in patients with T2DM. [8][9][10][11][12] Metformin has been reported to lead to malabsorption of vitamin B 12 and reduce its uptake in the terminal ileum, thereby decreasing the concentration of serum vitamin B 12 10-30%. 30 Manifestation of vitamin B 12 deficiency starts three to 6 months after starting use of metformin medication. ...
Objective:
To assess the association between vitamin B12 deficiency and the development of diabetic foot ulcers (DFU) in type 2 diabetes mellitus (T2DM).
Methods:
This is a case-control study that enrolled 323 Saudi adults with T2DM randomly selected from the Jazan Diabetes & Endocrine Center, Saudi Arabia from January 1, 2019, to July 31, 2019. The sample included 108 newly diagnosed cases with DFU and 215 control participants with T2DM unaffected by and free of foot ulcers (1:2 ratio). Logistic regression analysis was performed to determine the DFU predictors and to examine the association of DFU and vitamin B12 deficiency.
Results:
The highest DFU rates were found among the male participants and the participants older than 45 years. Neuropathy, vasculopathy, vitamin B12 deficiency, poor glycemic control, poor feet self-care, Charcot foot, physical inactivity, and spending long time standing at work were significantly associated with DFU, and all except physical inactivity and spending long time standing at work were independent predictors of DFU. After adjustment for the covariates, vitamin B12 deficiency was significantly associated with DFU (odds ratio 3.1), indicating that the patients with T2DM and vitamin B12 deficiency had a three times higher risk of developing DFU than those with normal vitamin B12 levels.
Conclusion:
Vitamin B12 deficiency had a significant association with DFU among the Saudi participants with T2DM. Establishing the causality and clarifying the biological role of vitamin B12 deficiency in DFU is important aims for future studies.
... 4 The drug, on the other hand, has been blamed for lowering B12 levels by up to 30%. 5 Multiple studies have found that Metformin-induced B-12 deficiency is caused by one or more of the following factors: decreased intestinal motility, disrupted B12 absorption from the gut, bacterial overgrowth, cobalamin-IF malfunction, and, last but not least, inhibited absorption of cobalamin-IF complex. 6,7 There is also a concurrent folate deficiency of unknown aetiology. Hyperhomocysteinemia develops as a result of double deficiency, resulting in vascular myocardial events. ...
Background: Diabetes mellitus is on the rise at an alarming rate, and it has now become a global issue. Type 2 Diabetic Mellitus is a disease characterized by disturbances in glucose, protein, and fat metabolism. Diabetes has been increasingly common in recent decades, causing significant socioeconomic burden, particularly in poorer countries. Objective: To investigate the prevalence of vitamin B12 deficiency in Type 2 diabetes patients taking metformin. Methodology: This study was conducted on T2 diabetic patients in the Diabetic Department of Diabetes and Endocrinology HMC Hospital, Peshawar, for a year (10 February 2019 to 12 March 2020). The demographic data of the recruited patients was obtained after they gave their informed written consent. Patients inquired about their metformin use history, dosage, and duration of type 2 diabetes mellitus. A 5cc venous blood sample was taken from the arm and kept at 4 degrees Celsius. Vitamin B12 levels were measured using enzyme-linked immunoassay assays after serum was withdrawn. ELISA was used to determine the Vitamin B12 level in serums. Results: A total of 149 people were enrolled in this trial. The patients' average age was 55 years. In this study, there were 67 (38.8%) males and 82 (55.2%) females. The individuals had a 5.12-year history of diabetes mellitus. The average HbA1c level was 8.280.32. The individuals that were included have taken metformin for at least 4.8 years. There were 25 (22.6%) patients using 1000-1500 mg metformin daily, 76 (46.4%) receiving 1500-2000 mg metformin daily, and 48 (40.7%) taking greater than 2000 mg metformin daily. There were 44 patients with a normal BMI, 80 patients who were overweight, and 25 patients who were obese. The average B12 level in the blood was 223pg/ml. Vitamin B12 deficiency was found in 96 (49.1%) of the patients. There was no vitamin B12 deficiency in 53 (45.4%) of the patients. Recommendations: It is strongly advised based on the findings of this study that Serum cobalamin levels should be measured in Type II diabetes patients who are taking metformin, and patients should be given R.D.A (Recommended Dietary Allowance) multivitamins to avoid sequaela of cobalamin deficiency.
... serum level of cobalamin and homocysteine in type 2 DM. Most of the past clinical studies demonstrated that metformin has some impact on plasma cobalamin and homocysteine and there are some case reports indicating deterioration of neuropathy with metformin[29][30][31][32] . Some recent researches have investigated the relation of metformin with the level of cobalamin and neuropathy with conflicting results29,33,34 . ...
Metformin-treated diabetics (MTD) showed a decrease in cobalamin, a rise in homocysteine, and methylmalonic acid, leading to accentuated diabetic peripheral neuropathy (DPN). This study aimed to determine whether or not metformin is a risk factor for DPN. We compared MTD to non-metformin-treated diabetics (NMTD) clinically using the Toronto Clinical Scoring System (TCSS), laboratory (methylmalonic acid, cobalamin, and homocysteine), and electrophysiological studies. Median homocysteine and methylmalonic acid levels in MTD vs. NMTD were 15.3 vs. 9.6 µmol/l; P < 0.001 and 0.25 vs. 0.13 µmol/l; P = 0.02, respectively with high statistical significance in MTD. There was a significantly lower plasma level of cobalamin in MTD than NMTD. Spearman’s correlation showed a significant negative correlation between cobalamin and increased dose of metformin and a significant positive correlation between TCSS and increased dose of metformin. Logistic regression analysis showed that MTD had significantly longer metformin use duration, higher metformin dose > 2 g, higher TCSS, lower plasma cobalamin, and significant higher homocysteine. Diabetics treated with metformin for prolonged duration and higher doses were associated with lower cobalamin and more severe DPN.
... Prospective studies pointed out a positive correlation between duration of treatment with MET and the development of peripheral neuropathy due to VB12 deficiency [20,23,24]. HOME study proved that a decrease in VB12 concentration associated to the use of MET is not a transitory phenomenon but progressive and persistent [25,26]. Unlike what was previously detailed, our study found no association between VB12 deficiency and time of exposure to any of the doses of MET. ...
... metallic taste in the mouth diarrhea nausea of vomiting swelling Double the appetite fast heart rate Headache It may cause anemia or cause a decrease in the absorption of vitamin B12. It also causes a condition called Lactic acid [15][16][17] ...
Simple sensitive methods to estimate the metformin hydrochloride. It works to reduce blood glucose level in NIDDM patients.
Metformin is a biguanide anti hyperglycemic agent. It works by decreasing glucose production by the liver and increasing the insulin
sensitivity of body tissues. Literature survey reveals analytical methods such as UV Spectrophotometry, liquid chromatography, gas
chromatography, GC-MS , flow injection fluorescence and flow injection MS/MS, have been reported for estimation of the metformin
hydrochloride in pharmaceutical formulations and biological fluids.
... The most widely accepted current mechanism suggests that MET antagonizes the calcium cation and interferes with the calcium-dependent IF-B 12 complex binding to the ileal cubilin receptor [8,9]. The recognition and treatment of B 12 deficiency is important because it is a cause of bone marrow failure, macrocytic anemia, and irreversible neuropathy [10]. ...
Metformin (MET) is currently being used in several trials for cancer prevention or treatment in non-diabetics. However, long-term MET use in diabetics is associated with lower serum levels of total vitamin B12. In a pilot randomized controlled trial of the Mediterranean diet (MedDiet) and MET, whose participants were characterized by different components of metabolic syndrome, we tested the effect of MET on serum levels of B12, holo transcobalamin II (holo-TC-II), and methylmalonic acid (MMA). The study was conducted on 165 women receiving MET or placebo for three years. Results of the study indicate a significant overall reduction in both serum total B12 and holo-TC-II levels according with MET-treatment. In particular, in the MET group 26 of 81 patients and 10 of the 84 placebo-treated subjects had B12 below the normal threshold (<221 pmol/L) at the end of the study. Considering jointly all B12, Holo-TC-II, and MMA, 13 of the 165 subjects (10 MET and 3 placebo-treated) had at least two deficits in the biochemical parameters at the end of the study, without reporting clinical signs. Although our results do not affect whether women remain in the trial, B12 monitoring for MET-treated individuals should be implemented.
... Limited research investigating these vitamins in relation to diabetes has been previously conducted, but one recent study also reported no association of metformin use with folate status (44). In contrast, interventions with metformin (ranging 16 weeks to 4 years) were found to decrease folate ADVANCE ARTICLE: concentrations modestly by 4 to 5% (45,46). The inconsistent findings regarding folate may relate to differences among studies in dietary intakes of fortified foods, known to provide a highly bioavailable folate form, i.e. folic acid (32). ...
Context
Emerging evidence suggests that deficiencies of folate-related B-vitamins can arise with metformin treatment and are independently linked with cognitive dysfunction, a co-morbidity of diabetes.
Objective
To determine the impact of hyperglycemia and metformin use on relevant B-vitamin biomarkers and cognitive outcomes in older adults.
Setting and Participants
Community-dwelling older people (74.1 ± 8.3 years, n = 4160) without dementia, recruited to the TUDA cohort study in 2008-2012, were classified as normoglycemic (n = 1856) or hyperglycemic, based on glycosylated hemoglobin (HbA1c) ≥ 5.7% (39 mmol/mol), either with (n = 318) or without (n = 1986) metformin treatment.
Main Outcome Measures
Biomarkers of folate, vitamin B12, vitamin B6 and riboflavin were measured. Cognitive assessments included the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) and the Frontal Assessment Battery (FAB).
Results
Metformin use was associated with higher risk of deficiency of vitamin B12 (combined B12 index ≤ -1; odds ratio (95% CI): 1.45 (1.03-2.02)) and vitamin B6 (plasma pyridoxal 5-phosphate <30.0 nmol/L; 1.48 (1.02-2.15)). Fortified foods when eaten regularly had a positive impact on all relevant B-vitamin biomarkers, even with hyperglycaemia. After adjustment for relevant co-variates, metformin use was associated with an increased risk of cognitive dysfunction as assessed using the RBANS (1.36 (1.03-1.80) and FAB (1.34 (1.03-1.74).
Conclusions
Use of metformin in older adults is associated with poorer cognitive performance; B-vitamin deficiency may be implicated. Fortified foods can optimize B-vitamin status and may be beneficial for maintaining better cognitive health in older people with or at risk of diabetes.
... 57 Metformin B12 vitamini emilim bozukluğu ve folat konsantrasyonlarının azalmasıyla ilişkilendirildiğinden uzun süreli tedavide B12 vitamini seviyeleri takip edilmelidir. 58 Metformin nadir ama ölümcül bir advers etki olan laktik asidoz ile ilişkilendirildiğinden laktik asidoz riski taşıyan hastalarda kontraendikedir. 57 PRAMLİNTİD Pramlintid, Tip 1 veya 2 diyabetli hastalarda insülin tedavisi ile birlikte kullanılmak üzere FDA tarafından onaylanan bir insan amilin analogudur. ...
... Drug Interactions On the long term of taking, Metformin decreases the absorption of vitamin B 12 . [80] [81] Renal eliminated drugs such as digoxin, ranitidine, trimethoprime and many others also has interaction with metformin way of elimination. ...
Many oral anti-hyperglycemic agents have been used for treatment of Type II diabetes (TY2D), yet Metformin, the only compound remained of biguanide derivates, continued to be used in this treatment. Its mechanism of action and pharmacokinetics are unique and significant. It has low side effects and no adverse incidences with healthy heart and kidney T2D, compared with its family group members. The previous properties made metformin tops the oral anti hyperglycemic agents list recommended from FDA in TY2D therapy. In this review paper, we aimed to point at bi-guanide development through time as glucose lowering agents, and show the magnificent characteristics of dimethylbiguanide; metformin. Abstract-Many oral anti-hyperglycemic agents have been used for treatment of Type II diabetes (TY2D), yet Metformin, the only compound remained of biguanide derivates, continued to be used in this treatment. Its mechanism of action and pharmacokinetics are unique and significant. It has low side effects and no adverse incidences with healthy heart and kidney T2D, compared with its family group members. The previous properties made metformin tops the oral anti hyperglycemic agents list recommended from FDA in TY2D therapy. In this review paper, we aimed to point at bi-guanide development through time as glucose lowering agents, and show the magnificent characteristics of dimethylbiguanide; metformin.
... Due to high cost of medical care and required treatments with long-term healing, diabetes is considered to be an economic burden and national public health problem that is of great concern [3]. According to the failure of conventional hypoglycaemic drugs to satisfactorily maintain normal glucose levels and some serious side effects [4][5][6], significant interest in alternative and complementary medicine, especially herbal preparations, has been maintained [7,8]. ...
Background
The Thai traditional herbal formula–Mathurameha, consisting of 26 medicinal plants, has been used as an alternative and complementary medicine for diabetes treatment in Wangnamyen Hospital, Thailand. To provide scientific evidences on the efficacy and safety of this herbal formula, in vivo hypoglycaemic activity, effect on serum biochemical profiles and acute toxicity were investigated.
Methods
Experimental type 2 diabetes was induced in male Sprague-Dawley rats by intraperitoneal injection of nicotinamide 15 min prior to intravenous injection of streptozotocin. The most effective extract from the oral glucose tolerant test (OGTT) was administered daily via the oral route to diabetic rats for 2 weeks. Two-hour postprandial plasma glucose (2h–PPG) levels were measured on days 0, 7, and 14. Biochemical data were measured at the end of daily oral administration experiment.
Results
Aqueous extract of the herbal formula was the most potent extract for improving glucose tolerance of streptozotocin-nicotinamide-induced diabetic rats after single oral administration. After 2 weeks of daily oral administration, the aqueous extract showed a dose-dependent glucose lowering effect. At doses of 12.5, 25, and 50 mg/kg, the 2h–PPG level of diabetic rats decreased by 3.32%, 15.78%, and 17.94%, respectively. Most of the biochemical profiles of diabetic rats were improved, including the total cholesterol (TC), alkaline phosphatase (ALP), total protein, albumin, globulin, creatinine, and uric acid levels. The significantly increased triglyceride (TG) level observed in treated diabetic rats indicated a lack of a beneficial effect of the extract on lipid homeostasis. Nevertheless, there were no signs or symptoms of acute toxicity observed after oral administration of aqueous extract (5 g/kg) to both male and female rats.
Conclusions
The results revealed that the herbal formula aqueous extract has hypoglycaemic activity, beneficial effects on biochemical profiles and a lack of acute toxicity. This study confirms the efficacy and safety of the Mathurameha herbal formula used for treating type 2 diabetes mellitus.
... Reactive oxygen species (ROS) overpowers the amount of neutralizing agents or antioxidants due to the case of oxidative stress. Endothelial dysfunctions and cardiovascular disease (CVD) which causes premature sickness and death in most countries which cause due to the formation of superoxide and the subsequent increase in oxidative stress [16]. The main purpose of treatment of diabetes is reduction in hyperglycemia by the use of insulin (in case of type 1 diabetics) and oral antihyperglycemics (e.g., biguanides, thiazolidinediones, sulfonylureas DPP-4 and α-glucosidase inhibitors etc.) either alone or in combination with insulin. ...
Background: The present study was designed to investigate the antihyperglycemic, antidyslipidemic effects and hepatoprotectivity of the fixed dose combination of metformin [850 mg/70 kg body weight (BW)] and pitavastatin [2 mg/70 kg (BW)] on alloxan induced (120 mg/kg BW) diabetic rats.
... Prolonged administration of metformin induces depletion of vitamin B 12 in blood serum (De Jager et al., 2010;Sullivan et al., 2011). According to the metabolic pathway folic acid, vitamin B 6 and B 12 influence the level of Homocysteine (Hcy) (Song, Cook, & Albert, 2009). ...
To explore the association of serum hyperhomocysteinaemia with 677C>T polymorphism in MTHFR gene among metformin-treated patients with type 2 diabetes. Serum-homocysteine levels of 227 diabetic subjects were measured before and after the metformin administration were analyzed statistically with respect to their genotype data for MTHFR 677C>T polymorphism. CC was the most prevalent genotype at MTHFR 677C>T in our sample and associated with the lowest homocysteine level. The patients with TT genotype had significantly elevated homocysteine compared with CC following metformin use (ORBaseline = 3.434 and 95% CI:0.622-4.127 vs. OREndpoint = 4.466 95% CI:3.124-5.53). A distinct statistical association between hyperhomocysteinaemia and the carriage of MTHFR 677C>T polymorphism was established among Indian diabetic patients who were treated with metformin. Our study underscores the importance of phamacogenetic analysis in diabetes-related therapeutics.
... 3 Another adverse effect associated with metformin that has been well documented and has the potential to cause long-term deleterious neurological and hematologic effects is vitamin B 12 malabsorption. [4][5][6][7] Approximately 30% of patients taking metformin do not properly absorb vitamin B 12 . 8 This effect is most often seen after the patient has received long-term treatment (ie, ≥6 months) and high doses (ie, >1 g/day) of metformin. ...
Background: Metformin may cause vitamin B12 deficiency that can present with symptoms of peripheral neuropathy. Lack of vitamin B12 serum concentration monitoring could result in vitamin B12 deficiency progression, worsening of symptoms, and unnecessary medication. Objectives: The purpose of this study was to (a) compare the influence of the rate of symptoms consistent with vitamin B12 deficiency on obtaining vitamin B12 serum concentrations in patients using metformin; (b) assess if vitamin B12 serum concentrations were ordered as a routine monitoring parameter. Methods: This retrospective case-control study evaluated patients receiving metformin. Patients in the case group had documented symptoms or diagnosis of peripheral neuropathy or macrocytic anemia, while those in the control group did not. The primary outcome was frequency of vitamin B12 serum concentration assessment. The secondary outcomes included frequency of vitamin B12 serum concentration assessment for patients presenting with symptoms or diagnosis of peripheral neuropathy or macrocytic anemia. Results: Analysis included 355 patients (116 cases, 239 controls). The cases were 5 times more likely to have a serum vitamin B12 serum concentrations drawn versus controls (odds ratio [OR] = 5.83, 95% confidence interval [CI] = 3.47-9.77, P < .001). Patients with a diagnosis of peripheral neuropathy or macrocytic anemia were 4 times more likely to have a serum vitamin B12 concentration drawn than those who did not (peripheral neuropathy: OR = 4.92, 95% CI = 2.95-8.21, P < .001; macrocytic anemia: OR = 5.41, 95% CI = 1.30-20.97, P = .007). Conclusions: Cases were more likely to have vitamin B12 serum concentrations assessed than patients without symptoms. The majority of patients taking metformin did not have routine vitamin B12 serum concentration assessments for medication adverse event monitoring.
... Metformin is considered a cornerstone in the treatment of diabetes and is the most frequently prescribed first line therapy for individuals with Type 2 diabetes [17]. It is one of a few antihyperglycaemic agents associated with improvements in cardiovascular morbidity and mortality which is a major cause of death in patients with Type 2 diabetes [18]. Metformin was approved by the Food and Drug Administration (FDA) for use in the United States in 1995 [19]. ...
... Previous studies reported metformin treatment was associated with a decrease in vitamin B12 concentration [34], which was present in 5.8% of the population [35] and vitamin B12 deficiency may be associated with hyperhomocysterinemia. However the association between vitamin B12 deficiency and deep vein thrombosis remained undetermined. ...
Metformin, an insulin-sensitizer, may correct several physiologic abnormalities owing to insulin resistance in patients with type 2 diabetes mellitus (DM). The effects of metformin on venous thrombosis in patient with type 2 DM have not been reported. Our study strived to explore the relationship of metformin therapy and the subsequent development of deep vein thrombosis (DVT) using a nationwide, population-based database.
From 1997 to 2003, we identified a study cohort consisting of patients with type 2 DM using metformin 7154 cases in the National Health Insurance Research Database. A control cohort without metformin, matched for age, sex, comorbidities, and medications was selected for comparison.
Of the 14945 patients (7167 patients with metformin vs. 7778 control), 60 (0.40%) patients developed DVT during a mean follow-up period of 3.74 years, including 16 (0.21%) from the cohort with metformin and 44 (0.56%) from the control group. Subjects with metformin experienced a 0.427 fold (95% confidence interval 0.240-0.758; P = 0.004) changes of risk reduction in development of DVT, which was independent of age, sex and co-morbidities. Kaplan-Meier analysis also revealed metformin therapy is associated with lower occurrence of DVT (log-rank test, P = 0.001).
Metformin may have protective effect in patients with type 2 DM for DVT.
... Un tratamiento de largo plazo con metformina puede asociarse a una disminución en la absorción intestinal de vitamina B12 y ácido fólico 29,30 . Se observó que la hemoglobina disminuyó en ambos grupos (metformina, p = 0,004 y el placebo, p = 0,016), siempre dentro de rangos normales. ...
In adults, metformin promotes weight loss and prevents the development of type 2 diabetes mellitus (DM2). However, these effects have not been demonstrated in adolescents at risk for DM2. Objective: To analyze the anthropometric and metabolic impact of metformin in obese adolescents at risk for DM2. Patients and Methods: A double-blind, placebo-controlled study was conducted in 19 obese female adolescents at risk for DM2. A structured lifestyle intervention with nutritional and exercise education and motivational support was assessed over 3 month with an additional follow up period of 3 months. Subjects were randomized to 500 mg/ daily of extended release metformin or placebo. Anthropometric (weight, BMI, waist circumference, blood pressure) and metabolic profiles (glycemia, HOMA, lipid profile, AST, ALT) were compared between both groups at the end of both periods. Results: Metformin treated group showed a significant reduction in weight and body mass index (BMI) compared with placebo group. No improvement in the metabolic risk profile was showed in any group. Conclusion: In this study, metformin therapy in combination with a lifestyle intervention helps to reduce weight and BMI in obese adolescent females at risk for DM2, compared to lifestyle and placebo intervention.
... Metformin has been postulated to induce malabsorption of vitamin B12 and intrinsic factor in the ileum [1], an effect that can be reversed by increasing calcium intake [2]. Jolien de Jager et al. demonstrated that long term metformin use increases the risk of vitamin B12 deficiency and that this negative effect increases over time [3]. Therefore we feel that this case highlights the possibility of this complication in patients on high dose metformin over an extended period of time and clinicians should be aware of this association and consider screening for vitamin B12 deficiency as it is easily treated. ...
Metformin is a commonly used oral hypoglycaemic agent worldwide. Gastrointestinal side effects and lactic acidosis related to metformin usage are commonly recognized. However, the associated vitamin B12 deficiency is less well known. We present a case of long term metformin use resulting in vitamin B12 deficiency
... If left untreated the neurological changes may become irreversible. Diabetic patients have specific risk factors with prolonged use of metformin being related to vitamin B12 deficiency [3]. ...
Vitamin B12 deficiency can confound the clinical assessment of patients presenting with features of spinal disorders. Speciality practice within spinal surgery may lead the clinician to a focus upon spinal explanations for symptoms and that belief may be reinforced by supporting imaging. In the presence of mainly sensory symptoms consideration and exclusion of non surgical causes needs to occur. This study aimed at identifying the prevalence of vitamin B12 deficiency; the presence of dual pathology on imaging performed; the implementation of replacement therapy and their subsequent clinical response as perceived by patients. This was performed through a retrospective review of patients presenting to specialist spine out-patient clinics over a 4-year period via access to pathology reports followed by a telephone survey. 457 patients were investigated of which 8.5% were vitamin B12 deficient. 70% of patients had repeat levels and 31% continued to be deficient. 26% of these patients were not placed on any supplemental therapy. 72% of patients on treatment had self perceived improved outcomes as compared with 55% not on treatment. 73% of patients underwent MRI/CT imaging. 59% of which had evidence of spinal stenosis. In older patients with sensory symptoms, the coexistence of B12 deficiency should be considered. Detection of deficiency with consequent treatment results in better global outcomes than no treatment. Unless the correct blood test is done, the pathology will remain undetected, and patients may continue with their primary symptoms despite high-risk spinal surgical procedures.
Diabetic Peripheral Neuropathy- prevalence, occurance, presentation, treatment
Liposomes, enclosed phospholipid vesicles with bilayered membrane structures, are effective and widely used encapsulation systems in the pharmaceutical and dietary supplement industries such as nutritional supplements. These encapsulating materials have attracted great attention due to their bioavailability, biodegradability, absence of toxicity, ability to deliver a wide variety of bioactive compounds, increasing ingredients solubility, and enhanced stability against a range of environmental, enzymatic, and chemical stresses. There has been rapid development of liposomes to carry different functional compounds known as supplements needed for a healthy life. In this chapter, the application of liposomes as emerging 236carrier vehicles of supplements such as minerals, vitamins, herbal extracts, essential fatty acids, and antioxidant compounds is discussed in detail.
Anaemia in older people is often underdiagnosed and undertreated despite being associated with increased morbidity and poor quality of life in older adults. Anaemia is typically classified by either underlying aetiology or morphology and size of red blood cells as determined by the mean‐corpuscular volume (MCV) of haemoglobin. In nutritional deficiencies, MCV is frequently in the normal range, particularly early in the disease course, and can be normal when multiple diseases are present concurrently, making it less useful for establishing an aetiology. The cornerstone of anaemia of chronic disease is underlying inflammation and excess production of cytokines. The definitive treatment of anaemia of chronic disease relies heavily on the eradication of the inflammatory or chronic disease process. A defining feature in anaemia of clonal disorders is stem cell mutations that lead to abnormal blood cell proliferation and progressive bone marrow failure.
Polycystic ovary syndrome (PCOS) is complex heteregeneous disorder which has several aspects in terms of pathology such as metabolic, endocrine, reproductive and psychological. However, the etiology of PCOS remains poorly understood. Several studies suggest that insulin resistance and hyperandrogenism play a central role in progression of PCOS pathophysiology. Therefore, common treatment strategies of PCOS are based on lifestyle modification which include exercise, diet and nutrient suplementation therapy. Recent studies have recommended some nutrients such as vitamins, minerals and vitamin like nutrients for therapy of PCOS because each one has at least one functional property in PCOS-induced pathways. Therefore, it is claimed that the reason of PCOS can be vitamin or mineral deficiency. This review aims to provide a critical literature survey on nutritional supplementation for the treatment of PCOS associated endocrine and metabolic dysfunctions and discuss the role of nutrients in management of PCOS in view of the clinical trials and experimental studies.
Nutritional deficiency of B12 is very common in pure vegetarians. Vegetarians suffering from type 2 Diabetes Mellitus and metformin treatment are predisposed to vitamin B12 deficiency and hence diabetic neuropathy and diabetic foot. We estimated B12 levels in patients with type 2 Diabetes Mellitus who are pure vegetarians on metformin therapy (cases), normal healthy individuals (controls). We found that B12 levels are significantly low in type 2 Diabetes Mellitus group when compared to control group with P<0.001 and 95% confidence intervals for mean being 201.65-227.60 and 583.90-802.88 in type 2 Diabetes Mellitus and controls respectively. Hence B12 estimation is necessary to identify B12 deficient patients. From several previous studies, we suggest that parenteral supplementation of vitamin B12 may help to prevent neuropathy, and diabetic foot in type 2 Diabetes Mellitus patients on metformin therapy. Clinical trials are required to establish the mode of supplementation of vitamin B12 for optimum clinical utility.
Type 2 diabetes mellitus (T2DM), is often associated with renal infections and complications, requiring antimicrobials. Metformin (Met) being the first line therapy in T2DM is co-administered with antimicrobial agents when infections coexist. Cefixime (Cef), an oral cephalosporin is effective in treatment of several bacterial infections. The current study investigated the effect of concurrent metformin-cefixime (Met-Cef) administration on glucose regulation, renal function and haematological indices in alloxan induced hyperglycaemic rats. Four groups of five wistar rats were used in the study. Groups I and II were normoglycemic receiving daily oral normal saline (10 ml/kg) and cefixime (400 mg/kg from day 14) respectively. Diabetes was induced with a single i.p. administration of 140 mg/kg alloxan monohydrate in groups III and IV which received 200 mg/kg metformin for 28 days, while group IV received cefixime in addition from day 15. Random blood glucose (RBG) was evaluated on days 8, 14 and 28, while fasting blood glucose (FBG) was evaluated on days 1, 14, 21 and 28. At the end of the study animals were humanely sacrificed and blood obtained was used for the determination of renal and haematological parameters. Relative weights of kidneys andpancreas were determined and histopathological evaluation of the organs also conducted. There was a statistically significant reduction(p
Patients with type 2 diabetes mellitus (T2DM) are usually treated with pharmacologic agents in combination with lifestyle modification. The development of new antidiabetic agents, such as insulin analogs and incretin-based therapies, has led to treatment strategies that enable many patients with T2DM to achieve target HbA(1c) levels (≤7.0%). However, many factors-including those related to the patient or the health-care provider, drug inadequacies and adverse effects-can interfere with the ability of some patients to reach metabolic targets. Clinical data from the USA indicate that HbA(1c) concentration, blood pressure and serum levels of lipids in patients with T2DM are progressively decreasing toward the target goals set by the American Diabetes Association. These improvements in metabolic regulation have led to a 30-40% decrease in reported microvascular and macrovascular complications of diabetes mellitus in the USA. Gastric bypass surgery in morbidly obese individuals with T2DM leads to remission of the diabetes mellitus in the majority of patients and improvement in the rest. A major contributor to this improvement is an alteration in gastrointestinal hormone secretions. Interventional surgery might, therefore, be considered a reasonable therapeutic alternative for overweight and obese (BMI <35 kg/m²) patients with T2DM who do not respond to medical therapy.
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