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(A) Correlation of vitamin B12 and metformin dose. (B) Correlation of Toronto Clinical Scoring System and metformin dose.
Source publication
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 Clinica...
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Citations
... Furthermore, metformin is posited to stimulate the expression of angiogenic factors in peripheral nerves. Consequently, patients who take metformin often reported neuropathy as a side effect of metformin (Hashem et al., 2021;Kim et al., 2019;Ni et al., 2017). ...
... MTHFR genetic variation combined with hyperhomocysteinemia was found to be associated (Mottaghi et al., 2019;Hsu et al., 2020). Previous studies confirmed that metformin consumption leads to peripheral neuropathy through B12 deficiency and high homocysteine (Elhadd et al., 2018;Hashem et al., 2021). Neuropathy impacts the quality of life and contributes to high morbidity and mortality rates among T2DM patients (Dornas et al., 2021;Hicks et al., 2021). ...
Neuropathy is the most common microvascular complication among type 2 diabetes mellitus (T2DM). Metformin consumption increases neuropathy risk. The Methylenetetrahydrofolate reductase (MTHFR) enzyme has confirmed its role in neuropathy. Metformin and MTHFR could decrease folate and induce hyperhomoscysteine. One of the common variants of the MTHFR gene is C677T and its located in the exon area. This study aimed to observe the association between variant C677T in the MTHFR gene and the risk of neuropathy among newly diagnosed T2DM patients with naive metformin. This cross-sectional study recruited 103 patients. The neuropathy risk was examined according to medical judgment through Neuropathy Symptom Score (NSS) and Neuropathy Disability Score (NDS) criteria. Genotyping C677T was performed using PCR-RFLP. This study found only one patient has a homozygote mutant, but more than 50% of patients were detected with allele mutants. There were no statistical differences in patient characteristics between CC and CT genotypes (p>0.05). Association between C677T and neuropathy risk was not significant statistically, either in the genotype model (p=0.97), allele model (p=0.82), and dominant model (p=0.91). There was still no significant association after adjusting for several confounding factors. We conclude that C677T in our population did not influence neuropathy risk. More specific criteria and laboratory parameters indicated neuropathy should be examined in the future study. Keywords: MTHFR, neuropathy, metformin, and T2DM
... 6,16,18 Hcy accumulation can lead to damage in the cardiovascular system, oxidative stress, neurotoxicity, and malignancy. 16,[18][19] Therefore, the aim of this study was to investigate the effect of metformin on serum VitB12 and Hcy levels and to determine the correlation between serum VitB12 and Hcy levels with the other study variables. ...
... 23 In the current study, the correlation between serum VitB12 level and metformin dose is insignificant. This result was also showed by Saber et al. 29 , and Alam et al 30 19 and Sugawara et al. 32 , who found a correlation between serum VitB12 level and metformin dose in the patients with diabetes. ...
... In addition, in this study, serum Vit B12 levels was insignificantly associated with the metformin use duration. This outcome is in agreement with the results of the study by Saber et al. 29 , Al Hamdi et al. 31 , Kim et al. 18 , Hashem et al. 19 and Sugawara et al. 32 . In the contrast to this finding are the results of the study by Miyan et al. [7] and Alam et al. (2021) 30 who showed a correlation between VitB12 level and metformin use duration. ...
Citation: AL-Ghaili SMA, Tayrab EMA, Obeagu EI. Effect of metformin on vitamin B12 and homocysteine levels among Sudanese with type 2 diabetes mellitus. Elite Journal of Medicine, 2024; 2(2): 85-103 Abstract Metformin is the first-line treatment for type 2 diabetes mellitus (T2DM), and hyperglycemia. When taken in high doses or for an extended period, metformin may decrease vitamin B12 (VitB12) level and may increase homocysteine (Hcy) level. There has been no research conducted in Sudan to determine whether metformin has an impact on VitB12 and Hcy levels in individuals withT2DM. The aim of this research is to investigate the effect of metformin on VitB12 and Hcy levels among Sudanese with T2DM. This cross-sectional study included 98 Sudanese with T2DM who had been taking metformin for at least a year. Data analysis was carried out using SPSS V-26. This study found that 1 patient (1%) had a VitB12 deficiency (< 180 pg/mL), 52 (53.1%) subjects had a normal VitB12 level (180-900 pg/mL), and 45 (45.9%) subjects had VitB12 ≥ 900 pg/mL. One patient (2.9%) had an Hcy deficiency (< 3µmol/l) and 34 (97.1%) subjects had a normal Hcy level (3-15 µmol/L). The study showed a, significant negative correlation between VitB12 and vitamin supplements (P = 0.003) and metformin combined with insulin (P = 0.000). Although that belongs to the subgroup that took vitamin supplements, there was a significant positive correlation between VitB12 and metformin alone (P = 0.006) and a significant negative association with metformin combined with insulin (P = 0.000). In the subgroup that did not take vitamin supplements, there was a significant positive correlation between VitB12 and FBS (P = 0.001). There was an insignificant correlation between VitB12 and the metformin dose and use duration. The correlation between VitB12 and Hcy levels was insignificant in the entire group and Elite Journal of Medicine. Volume 2 issue 2(2024), Pp. 85-103 https://epjournals.com/journals/EJM Citation: AL-Ghaili SMA, Tayrab EMA, Obeagu EI. Effect of metformin on vitamin B12 and homocysteine levels among Sudanese with type 2 diabetes mellitus. Elite Journal of Medicine, 2024; 2(2): 85-103 2 in both subgroups. The correlation between Hcy levels and metformin use duration was significantly negative (P = 0.015), but the correlation between Hcy levels and metformin dose was insignificant. In Sudanese with T2DM and under metformin treatment, serum VitB12 level was positively and significantly correlated with DM duration and (FBS), was significantly and negatively correlated with vitamin supplements. On the conversely, serum homocysteine (Hcy) levels significantly decreased with metformin use duration.
... Hyperhomocysteinemia is a biomarker for predicting tissue Cbl de ciency and is a risk indicator for DM complications, diabetic neuropathy (DNP), and cardiovascular illnesses [6,16,18] . Hcy accumulation can lead to damage in the cardiovascular system, oxidative stress, neurotoxicity, and malignancy [16,18,19] . ...
... In the current study, the correlation between serum VitB12 level and metformin dose is insigni cant. This result was also showed by Saber et al. (2019) [29] , and Alam et al (2021) [30] , but this nding in contrast to ve previous studies reported by Miyan et al (2020) [7] , Al Hamdi et al. (2020) [31] , Kim [19] and Sugawara et al. (2020) [32] , who found a correlation between serum VitB12 level and metformin dose in the patients with diabetes. ...
... In addition, in this study, serum VitB12 levels was insigni cantly associated with the metformin use duration. This outcome is in agreement with the results of the study by Saber et al. (2019) [29] , Al Hamdi et al. (2020) [31] , Kim et al. (2019) [18] , Hashem et al. (2021) [19] and Sugawara et al. (2020) [32] . In the contrast to this nding are the results of the study by Miyan et al. (2020) [7] and Alam et al. (2021) [30] who showed a correlation between VitB12 level and metformin use duration. ...
Background: Metformin is the first-line treatment for type 2 diabetes mellitus (T2DM), and hyperglycemia. When taken in high doses or for an extended period, metformin may decrease vitamin B12 (VitB12) level and may increase homocysteine (Hcy) level. There has been no research conducted in Sudan to determine whether metformin has an impact on VitB12 and Hcy levels in individuals withT2DM.
The aim of this research is to investigate the effect of metformin on VitB12 and Hcy levels among Sudanese with T2DM.
Methods: This cross-sectional study included 98 Sudanese with T2DM who had been taking metformin for at least a year. Data analysis was carried out using SPSS V-26.
Results: This study found that 1 patient (1%) had a VitB12 deficiency (< 180 pg/mL), 52 (53.1%) subjects had a normal VitB12 level (180 - 900 pg/mL), and 45 (45.9%) subjects had VitB12 ≥ 900 pg/mL. One patient (2.9%) had an Hcy deficiency (< 3µmol/l) and 34 (97.1%) subjects had a normal Hcy level (3–15 µmol/L). The study showed a, significant negative correlation between VitB12 and vitamin supplements (P = 0.003) and metformin combined with insulin (P = 0.000). Although that belongs to the subgroup that took vitamin supplements, there was a significant positive correlation between VitB12 and metformin alone (P = 0.006) and a significant negative association with metformin combined with insulin (P = 0.000). In the subgroup that did not take vitamin supplements, there was a significant positive correlation between VitB12 and FBS (P = 0.001). There was an insignificant correlation between VitB12 and the metformin dose and use duration. The correlation between VitB12 and Hcy levels was insignificant in the entire group and in both subgroups. The correlation between Hcy levels and metformin use duration was significantly negative (P = 0.015), but the correlation between Hcy levels and metformin dose was insignificant.
Conclusions: In Sudanese with T2DM and under metformin treatment, serum VitB12 level was positively and significantly correlated with DM duration and (FBS), was significantly and negatively correlated with vitamin supplements. On the conversely, serum homocysteine (Hcy) levels significantly decreased with metformin use duration.
... However, treating hyperglycemia, in particular, does not slow the progression of DPN in those with type 2 diabetes [29] because DPN is irreversible. Similar to DR pathogenesis, DPN pathogenesis involves oxidative stress and inflammatory mechanisms that have been shown to harm neural tissues [30]. ...
Diabetes mellitus (DM), one of the most serious non-communicable diseases, has long-term negative effects on the healthcare system due to its microvascular and macrovascular manifestations, which can be fatal if left untreated. Nutraceuticals, on the other hand, are alternative therapy choices of orally consumed natural food ingredients applicable in the management of several diseases, including diabetes mellitus. Through their antioxidant capabilities and bioactive components, nutraceuticals have been clinically demonstrated to be effective in preventing a number of ailments, including cancer, diabetes, heart disease, and kidney problems. Flavonoids, which are categorized as phytochemicals, are present in several of these nutraceuticals. Cocoa, one of the flavanols engaged in the treatment of diabetes mellitus, provides an additional non-pharmaceutical intervention in the management of diabetes mellitus, which, in part, is because of its high antioxidant capacity. Additionally, flavonoids improve insulin resistance and sensitivity, dyslipidemia, endothelial function, and blood pressure, as well as lower oxidative stress and inflammatory processes. As a result, they may be able to stop the progression of long-term vascular consequences of diabetes, such as cardiovascular disease, neuropathy, nephropathy, and retinopathy. Therefore, the effects of nutraceuticals (as an alternative treatment) on diabetic-related micro- and macrovascular problems are the main focus of this review.
... Diabetic peripheral neuropathy (DPN) stands out as one of the most prevalent complications associated with type 2 diabetes mellitus (T2DM) (6). Clinically, DPN presents with a range of distressing symptoms primarily affecting the distal limbs and motor function. ...
Background
The anticipation of diabetes-related complications remains a challenge for numerous T2DM patients, as there is presently no effective method for early prediction of these complications. This study aims to investigate the association between renal function-related indicators and the occurrence of peripheral neuropathy and retinopathy in individuals diagnosed with type 2 diabetes mellitus (T2DM) who currently have normal renal function.
Methods
Patients with T2DM who met the criteria were selected from the MMC database and divided into diabetic peripheral neuropathy (DPN) and diabetic retinopathy (DR) groups, with a total of 859 and 487 patients included, respectively. Multivariate logistic regression was used to analyze the relationship between blood urea nitrogen (BUN), creatinine (Cr), uric acid (UA), urine albumin(ALB), albumin-to-creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), and diabetic peripheral neuropathy and retinopathy. Spearman correlation analysis was used to determine the correlation between these indicators and peripheral neuropathy and retinopathy in diabetes.
Results
In a total of 221 patients diagnosed with DPN, we found positive correlation between the prevalence of DPN and eGFR (18.2, 23.3, 35.7%, p < 0.05). Specifically, as BUN (T1: references; T2:OR:0.598, 95%CI: 0.403, 0.886; T3:OR:1.017, 95%CI: 0.702, 1.473; p < 0.05) and eGFR (T1: references; T2:OR:1.294, 95%CI: 0.857, 1.953; T3:OR:2.142, 95%CI: 1.425, 3.222; p < 0.05) increased, the odds ratio of DPN also increased. Conversely, with an increase in Cr(T1: references; T2:OR:0.86, 95%CI: 0.56, 1.33; T3:OR:0.57, 95%CI: 0.36, 0.91; p < 0.05), the odds ratio of DPN decreased. Furthermore, when considering sensitivity and specificity, eGFR exhibited a sensitivity of 65.2% and specificity of 54.4%, with a 95% confidence interval of 0.568–0.656.
Conclusion
In this experimental sample, we found a clear positive correlation between eGFR and DPN prevalence.
... Deficiencies in both vitamins are related to an increased risk of depression in adults [36]. In diabetic individuals with neuronal involvement, metformin-induced vitamin B12 deficiency can worsen nerve damage, leading to neuropathy caused by cobalamin deficiency [37]. Furthermore, moderate to severe peripheral neuropathy associated with diabetes occurred much more frequently in metformin-treated individuals [37]. ...
... In diabetic individuals with neuronal involvement, metformin-induced vitamin B12 deficiency can worsen nerve damage, leading to neuropathy caused by cobalamin deficiency [37]. Furthermore, moderate to severe peripheral neuropathy associated with diabetes occurred much more frequently in metformin-treated individuals [37]. ...
Diabetes mellitus (DM) is the most common metabolic disease worldwide. Hence, the prevalence of the disease continues to increase across the globe. Metformin is used as a first-line oral hypoglycemic drug to keep control of type-2 DM (T2DM) in adults. Diabetic patients on metformin have been largely seen to be suffering from a deficiency of vitamin B12. It is a water-soluble vitamin mainly obtained from animal food like meat. At the basic cell level, it acts as a cofactor for enzymes essential for DNA synthesis and neuroprotection. As a result, vitamin B12 deficiency can show clinical effects such as progressive demyelination, peripheral neuropathy and haematological abnormalities (such as macrocytic anaemia and neutrophil hypersegmentation). Various studies also show a relation between vitamin B12 insufficiency and metformin-treated T2DM patients as decreased absorption of vitamin B12. There could be a severe complication of vitamin B12 deficiency in T2DM patients. The use of proton pump inhibitors, gastric bypass surgery, older patients and patients with a higher red blood cell turnover are factors that hasten the depletion of vitamin B12 reserves in the liver. Methylmalonic acid and homocysteine levels can be measured to identify vitamin B12 insufficiency at its early stage if blood vitamin B12 levels are borderline. The action of metformin on vitamin B12 absorption and its potential mechanisms of inhibition will be the main topics of discussion in this review. The review will also discuss how vitamin B12 deficiencies in T2DM patients using metformin affect their clinical results.
... Peripheral neuropathy (PN) affects 60-70% of patients with diabetes, and metformin use is a risk factor for the development of diabetic PN. 28 The global incidence of PN is expected to rise as a result of the projected increase in the number of patients with diabetes, from 451 million people in 2017 to 693 million people by 2045. 29 Furthermore, an estimated 49.7% of the people living with diabetes remain undiagnosed. ...
... 40 Another study has also shown that patients with symptomatic have been reported to be two to three times more likely to develop PN. 31 Prolonged use and higher doses of metformin in patients with diabetes were also associated with vitamin B12 deficiency, increased homocysteine (Hcy) and methylmalonic acid (MMA), which are associated with increased diabetic PN severity. 28 The metformin usage index (MUI) can be used as a risk assessment tool for the evaluation of vitamin B12 deficiency and PN in patients with type 2 diabetes. For instance, an MUI > 5 suggests a high risk of vitamin B12 deficiency. ...
Introduction:
Peripheral neuropathy (PN) is an insidious disease that is often asymptomatic during the early stages but which can have a significant impact on quality of life at later stages when nerve damage occurs. There is currently no guidance on the use of neurotropic B vitamins (B1, B6, and B12) for the management of asymptomatic and symptomatic PN.
Objective:
To provide guidance to primary care physicians on an integrated approach to managing PN with neurotropic B vitamins (B1, B6, and B12).
Materials and methods:
A multidisciplinary panel of eight experts participated in an iterative quasi-anonymous Delphi survey consisting of two rounds of questions and a virtual meeting. A literature review formed the basis of the survey questions. The first round included multiple select, qualitative, and Likert Scale questions; the subsequent round consisted of 2-point scale (agree or disagree) questions that sought to develop consensus-based statements refined from the first round and recommendations derived from discussions during the virtual expert panel meeting.
Results:
Clinical recommendations for the use of neurotropic B vitamins (B1, B6, and B12) have been developed for the prevention of PN progression or to delay onset in patients at high risk of developing PN. Recommendations have also been provided for the assessment of PN etiology and considerations for the use of loading dose (high dose) and maintenance dose (lower dose) of these neurotropic B vitamins (B1, B6, and B12).
Conclusion:
These clinical recommendations provide an initial step towards formulating comprehensive guidelines for the early and long-term management of PN with neurotropic B vitamins (B1, B6, and B12) and move beyond addressing only neuropathic pain associated with the late stages of PN.
... Brazilian Journal of Health Review, Curitiba, v. 6, n. 3, p.9534-9548, may./jun., 2023 [11,14,15,18,20,21]. ...
... Of the 14 studies described in Table I, 13 studies showed that the use of metformin, which is a hypoglycemic medication widely used in the treatment of T2DM, is intrinsically linked to considerably reduced levels of serum vitamin B12 [6,[10][11][12][13][14][15][16][17][18][19][20][21]. ...
... Metformin therapy is the first option for the treatment of T2DM and long-term therapy with the hypoglycemic agent (more than 2 years) has been shown to significantly reduce plasma levels of vitamin B12, which can lead to PN, cognitive impairment, and subacute bone marrow degeneration with macrocytic anemia. Even short-term therapy is capable of promoting a decrease in serum levels of vitamin B12 and folic acid, as well as an increase in homocysteine Most of the studies shown in Table I related treatment with metformin to the reduction of serum levels of vitamin B12, increasing, according to the authors, the chances of developing PN [6,[11][12][13][14][15][16][17][18][19][20][21]. Thus, although no direct relationship was found between vitamin B12 deficiency and PN in these studies, the authors define vitamin deficiency as a probable risk factor. ...
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.
... It is a dimethyl biguanide derivative that has been used in medicine since 1957 as an oral antidiabetic drug in the treatment of type 2 diabetes, especially in obese or overweight patients. When used in elderly patients, it increases life expectancy and reduces cognitive impairment [215]. In addition, metformin has a positive effect on the mitochondria of nerve cells, inhibiting the process of their damage, thus extinguishing the inflammation developing on the basis of ROS activity and oxidative stress [216]. ...
Alzheimer’s disease is one of the most commonly diagnosed cases of senile dementia in the world. It is an incurable process, most often leading to death. This disease is multifactorial, and one factor of this is inflammation. Numerous mediators secreted by inflammatory cells can cause neuronal degeneration. Neuritis may coexist with other mechanisms of Alzheimer’s disease, contributing to disease progression, and may also directly underlie AD. Although much has been established about the inflammatory processes in the pathogenesis of AD, many aspects remain unexplained. The work is devoted in particular to the pathomechanism of inflammation and its role in diagnosis and treatment. An in-depth and detailed understanding of the pathomechanism of neuroinflammation in Alzheimer’s disease may help in the development of diagnostic methods for early diagnosis and may contribute to the development of new therapeutic strategies for the disease.
... However, the outcomes of studies, using Metformin as symptomatic treatment of diabetic neuropathy, is not consistent with pre-clinical studies. Many studies have mentioned that vitamin B12 deficiency caused by Metformin use in diabetic patients can cause and even worsen diabetic neuropathy and should be carefully noticed in diabetic population [49][50][51][52][53][54]. ...
... Hashem et al mentioned that using Metformin could worsen diabetic neuropathy in patients with type 2 DM [52]. Luo et al also mentioned that Metformin administration in type 2 DM patients was associated with higher incidence of developing diabetic PN. ...
... However, there are concerns about using Metformin as an adjuvant for the treatment of PN. To date, many clinical studies suggested that long-term use of Metformin, especially over 5 years and higher cumulative dose of Metformin is associated with vitamin B12 deficiency, which can cause progression of central and peripheral neuropathy [49][50][51][52][53][54]. Contrary to initial disappointing results, Russo et al mentioned that in type 2 DM patients who received Metformin for at least 6 months, vitamin B12 deficiency was just mild and didn't have a relationship with developing diabetic neuropathy [76]. ...
Purpose: Despite the troublesome nature of Peripheral Neuropa-thy (PN) and the possibility of irreversible complications, there is still no approved strategy for the treatment of PN. However, some atypical analgesic agents such as gabapentin, pregabalin, and duloxetine have beneficial effects. Metformin is an anti-hyperglycemic agent which is widely used for the treatment of type 2 Diabetes Mellitus (DM). In addition to its blood sugar-lowering effect, many studies have suggested that Metformin has beneficial effect in the suppression of inflammation by many mechanisms. Regarding, several studies have been conducted on the effectiveness of Metformin in the prevention or controlling the symptoms of PN. The aim of this article is to review the potential effect of Metformin as an adjuvant for the treatment of PN with a focus on diabetic neuropathy and CIPN. Methods: In this paper, the researcher has conducted a search on PubMed and Scopus, and Web of Science for original articles and reviews published from 1993 until 2022, with the following keywords; Peripheral Neuropathy, Diabetic Neuropathy, Metformin and Post-Che-motherapy complications. Results: We identified 79 studies at the first step of search strategy. Finally, 17 studies were included, of which 12 were animal studies and 5 were human studies. Conclusion: In-Vitro and animal studies have shown beneficial effects of Metformin controlling the development of peripheral neuropa-thy. However, clinical results of using Metformin for symptomatic treatment of diabetic neuropathy is conflicting. Further clinical studies are needed to establish the effect of metformin on peripheral neuropathy. Citation: Moghaddam NS, Tebbi M, Borhaninia M, Gharibi S, Arasteh O, et al. Peripheral neuropathy: A review of mechanism based treatments with a focus on metformin as a possible choice.
