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      Vitamin B12 deficiency and diabetic neuropathy in patients taking metformin: a cross-sectional study

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          Abstract

          Objective

          Vitamin 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.

          Methods

          A 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.

          Results

          Low 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).

          Conclusions

          Vitamin 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.

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          Most cited references25

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          Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy

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            Validation of Michigan neuropathy screening instrument for diabetic peripheral neuropathy.

            The reliability and accuracy of the Michigan neuropathy screening instrument (MNSI) have been discussed recently. As a result of the difficulties of performing and analyzing nerve biopsy as a standard diagnostic test, electromyography and neuronography is used as the best alternative diagnostic procedure. The objective of this study was to determine the diagnostic performance of the test characteristics and cut-off point of MNSI scoring for the diagnosis of diabetic peripheral neuropathy. Over a 2-year period, a cross-sectional study was conducted on 176 type 2 diabetic patients. An internist carried out the MNSI and the sum of scores varying from 0 to 1 for each abnormality as revealed in foot appearance, ulceration, ankle reflexes and vibratory perception has been recorded. A neurologist, who was blind to the MNSI scores, performed all neurophysiological studies. The test performance characteristics of the MNSI procedure were measured for different cut-off values. MNSI scores of 1.5, 2.0, 2.5 and 3.0 were assessed as cut-off values. Sensitivities were 79%, 65%, 50% and 35% and specificities were 65%, 83%, 91% and 94%, respectively. Positive predictive values increased and negative predictive values decreased for each score. Accuracies, likelihood ratios and post-test probabilities were measured. The accuracy of MNSI scoring makes it a useful screening test for diabetic neuropathy in taking a decision regarding which patients should be referred to a neurologist for electrophysiological studies. High specificity, likelihood ratios over 5 and a moderate to good post-test probability give a high diagnostic impact for MNSI scoring. We suggest a cut-off point of 2 for the MNSI procedure. However, electrophysiological studies should be considered when the patient has signs and symptoms other than those rated by the MNSI, suggesting peripheral nerve involvement, and also because the MNSI is still just a screening test.
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              Risk factors of vitamin B(12) deficiency in patients receiving metformin.

              Identification of risk factors for metformin-related vitamin B(12) deficiency has major potential implications regarding the management of diabetes mellitus. We conducted a nested case-control study from a database in which the source population consisted of subjects who had levels of both serum vitamin B(12) and hemoglobin A(1c) checked in a central laboratory. We identified 155 cases of diabetes mellitus and vitamin B(12) deficiency secondary to metformin treatment. Another 310 controls were selected from the cohort who did not have vitamin B(12) deficiency while taking metformin. A total of 155 patients with metformin-related vitamin B(12) deficiency (mean +/- SD serum vitamin B(12) concentration, 148.6 +/- 40.4 pg/mL [110 +/- 30 pmol/L]) were compared with 310 matched controls (466.1 +/- 330.4 pg/mL [344 +/- 244 pmol/L]). After adjusting for confounders, we found clinically important and statistically significant association of vitamin B(12) deficiency with dose and duration of metformin use. Each 1-g/d metformin dose increment conferred an odds ratio of 2.88 (95% confidence interval, 2.15-3.87) for developing vitamin B(12) deficiency (P<.001). Among those using metformin for 3 years or more, the adjusted odds ratio was 2.39 (95% confidence interval, 1.46-3.91) (P = .001) compared with those receiving metformin for less than 3 years. After exclusion of 113 subjects with borderline vitamin B(12) concentration, dose of metformin remained the strongest independent predictor of vitamin B(12) deficiency. Our results indicate an increased risk of vitamin B(12) deficiency associated with current dose and duration of metformin use despite adjustment for many potential confounders. The risk factors identified have implications for planning screening or prevention strategies in metformin-treated patients.

                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                October 2019
                13 September 2019
                : 8
                : 10
                : 1324-1329
                Affiliations
                [1 ]Endocrinology Program , Facultad de Medicina y Ciencias de la Salud, Universidad Militar Nueva Granada,Bogotá, Colombia
                [2 ]Endocrinology Department , Hospital Militar Central, Bogotá, Colombia
                [3 ]Endocrinology Department , Hospital Militar Central, Bogotá , Colombia
                [4 ]Investigation Department , Epidemiology, Hospital Militar Central, Bogotá, Colombia
                [5 ]Investigation Department , Statistics, Hospital Militar Central, Bogotá, Colombia
                Author notes
                Correspondence should be addressed to M Alvarez: mauricioalvarez613@ 123456gmail.com
                Article
                EC-19-0382
                10.1530/EC-19-0382
                6790897
                31518991
                265d484d-dbb5-4d6b-af97-d8575de57521
                © 2019 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                History
                : 08 September 2019
                : 13 September 2019
                Categories
                Research

                vitamin b12,metformin,diabetes mellitus,prediabetic state,malabsorption,syndromes,diabetic neuropathies

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