Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: A systematic review and meta-analysis

Chapman, Leon; Darling, A. L.; Brown, Jonathan E.

doi:10.1016/j.diabet.2016.03.008

Cited by 170 publications

(166 citation statements)

References 48 publications

(71 reference statements)

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“…Recently in the USA, a large community survey (25,956 cases and 184,199 controls) found that the long term use (>2 years) of H 2 RAs and PPIs was associated with a 25%–65% greater risk of a subsequent diagnosis of vitamin B12 deficiency [45]. In addition, metformin usage in Type 2 Diabetes can also result in vitamin B12 deficiency, possibly interfering with calcium-dependent membrane action in the terminal ileum required for the absorption of the vitamin B12-intrinsic factor complex [46,47]. …”

Section: Causes Of B-vitamin Deficiencymentioning

confidence: 99%

Causes, Consequences and Public Health Implications of Low B-Vitamin Status in Ageing

et al. 2016

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The potential protective roles of folate and the metabolically related B-vitamins (vitamins B12, B6 and riboflavin) in diseases of ageing are of increasing research interest. The most common cause of folate and riboflavin deficiencies in older people is low dietary intake, whereas low B12 status is primarily associated with food-bound malabsorption, while sub-optimal vitamin B6 status is attributed to increased requirements in ageing. Observational evidence links low status of folate and the related B-vitamins (and/or elevated concentrations of homocysteine) with a higher risk of degenerative diseases including cardiovascular disease (CVD), cognitive dysfunction and osteoporosis. Deficient or low status of these B-vitamins alone or in combination with genetic polymorphisms, including the common MTHFR 677 C → T polymorphism, could contribute to greater disease risk in ageing by causing perturbations in one carbon metabolism. Moreover, interventions with the relevant B-vitamins to optimise status may have beneficial effects in preventing degenerative diseases. The precise mechanisms are unknown but many have been proposed involving the role of folate and the related B-vitamins as co-factors for one-carbon transfer reactions, which are fundamental for DNA and RNA biosynthesis and the maintenance of methylation reactions. This review will examine the evidence linking folate and related B-vitamins with health and disease in ageing, associated mechanisms and public health implications.

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Section: Causes Of B-vitamin Deficiencymentioning

confidence: 99%

Causes, Consequences and Public Health Implications of Low B-Vitamin Status in Ageing

et al. 2016

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“…Recently, a meta-analysis by Chapman et al reported an association of low vitamin B12 plasma levels in patients with diabetes [7]. A mean difference in vitamin B12 levels in metformin versus controls of 57pmol/L after 6 weeks to 3 months of use in patients with type 2 diabetic was seen (fixed weighted mean difference, −0.57; 95%CI, −35 to 79pmol/L)[7].…”

Section: Introductionmentioning

confidence: 99%

“…A mean difference in vitamin B12 levels in metformin versus controls of 57pmol/L after 6 weeks to 3 months of use in patients with type 2 diabetic was seen (fixed weighted mean difference, −0.57; 95%CI, −35 to 79pmol/L)[7]. A meta-analysis by Niafar et al identified an increased incidence of vitamin B12 deficiency in diabetic patients, defined as levels <150pmol/L, (OR=2.45, 95%Confidence interval, CI 1.74 to 3.44, p<0.0001) as well as lower mean vitamin B12 levels in those who received metformin (mean difference= −65.8, 95%CI −78.1 to −53.6 pmol/L, p<0.00001) versus control [8].…”

Section: Introductionmentioning

confidence: 99%

Effects of metformin versus placebo on vitamin B12 metabolism in non-diabetic breast cancer patients in CCTG MA.32

Lohmann

Liebman

Brien

et al. 2017

Breast Cancer Res Treat

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Background Metformin is associated with low levels of vitamin B12 (VitB12) in patients with diabetes. The CCTG/MA.32 trial investigates effects of metformin vs placebo on breast cancer (BC) outcomes in non-diabetic high risk BC patients. We analyzed VitB12 at baseline and after 6 months of metformin (versus placebo) in the first 492 patients with paired blood samples. Methods VitB12 was analyzed centrally in baseline and 6 month fasting plasma. Levels<181pmol/L were considered deficient, 181 to 221pmol/L borderline and ≥ 222pmol/L sufficient. Methylmalonic acid(MMA) and homocysteine (HC) were assayed in those with VitB12 levels<222pmol/L. Statistical analyses used Spearman’s ranked correlation coefficients and the Wilcoxon signed rank test for continuous variables and Chi-square test for categorical variables. Results 237 patients received metformin and 255, placebo; Median (Inter Quartile Range) baseline VitB12 levels were 390(290, 552) and 370(290, 552) pmol/L in the metformin and placebo arms, respectively, (p=0.97). At six months, the median levels were 320(244, 419) in the metformin versus 380(286, 546) pmol/L in the placebo arm (p=0.0001). At baseline, 15 patients (11 metformin and 4 placebo) had VitB12<181pmol/L; at 6 months, 18 patients (15 metformin and 3 placebo) (p=0.004). Median hemoglobin was similar at baseline, metformin, 130g/L (124-137), and placebo arms, 131g/L (124-137), (p=0.38) and at 6 months, metformin, 131g/L (91-162), and 131g/L (106-169) in placebo group, (p=0.11). Of the 74 subjects with vitamin B12<222pmol/L at either time point (45 metformin, 29 placebo), at baseline MMA was normal in all patients and 2 had elevated HC (>15umol/L). At 6 months, 1 patient (metformin) had MMA >0.4umol/L and 3 (2 metformin, 1 placebo) had HC>15umol/L. Conclusions There was an increased rate of biochemical VitB12 deficiency after 6 months of metformin; this was not associated with anemia. Further research will investigate VitB12 levels in all subjects at baseline, 6 and 60 months.

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“…Only in 2016 Chapman et al performed a systematic review and a meta-analysis of results of studies (observational and interventional) concerning the relationship between metformin and vitamin B 12 deficiency carried out on a homogeneous group of type 2 diabetic patients [27]. …”

Section: Potential Mechanisms Of Vitamin B 12 Deficiencymentioning

confidence: 99%

Is it necessary to be afraid of vitamin B12 deficiency during metformin treatment?

Gumprecht

Długaszek

Niemczyk

et al. 2017

Clinical Diabetology

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Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: A systematic review and meta-analysis

Cited by 170 publications

References 48 publications

Causes, Consequences and Public Health Implications of Low B-Vitamin Status in Ageing

Causes, Consequences and Public Health Implications of Low B-Vitamin Status in Ageing

Effects of metformin versus placebo on vitamin B12 metabolism in non-diabetic breast cancer patients in CCTG MA.32

Is it necessary to be afraid of vitamin B12 deficiency during metformin treatment?

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