The role of metformin on vitamin B12 deficiency: a meta-analysis review

Abstract

Metformin is the only biguanide oral hypoglycemic drug, that is used to treat patients with type-2 diabetes mellitus. There are some reports of metformin being associated with decreased serum levels of vitamin B12 (VB12). The objective of this study is to systematically analyze the impact of metformin on the frequency of VB12 deficiency and serum levels of VB12. A search of various databases provided 18 retrospective cohort studies and 11 randomized controlled trials. Pooled estimates of odds ratio with 95% confidence interval using random effect model were conducted. Studies were examined for heterogeneity, publication bias and sensitivity analysis. Separate analysis of randomized control trials (RCTs) including both low-risk and high-risk bias was also conducted. 29 studies were selected with a total of 8,089 patients. 19 studies were rated intermediate or high quality. Primary outcome suggested increased incidence of VB12 deficiency in metformin group (OR = 2.45, 95% CI 1.74-3.44, P < 0.0001.) Heterogeneity was relatively high (I(2) = 53%), with minor publication bias. Secondary outcome suggested lower serum VB12 concentrations in metformin group (Mean difference = -65.8, 95% CI -78.1 to -53.6 pmol/L, P < 0.00001) with high heterogeneity (I(2) = 98%,) and low publication bias. RCTs analysis of low-and high-risk group revealed similar trends. We conclude that metformin treatment is significantly associated with an increase in incidence of VB12 deficiency and reduced serum VB12 levels.

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

“…Most intervention trials in this review were only of short duration (up to 4-months) but indicated a statistically significant reduction in B12 levels beyond the 6-weeks period and in some cases led to frank deficiency. Our fixed effects meta-analysis of four intervention trials showed a statistically significant lowering of vitamin B12 levels by 57 pmol/L(95% CI: -35 to -79).This reduction in B12 levels could be clinically significant in causing frank deficiency In terms of previous research, our results supports the recent meta-analysis by Niafar et al(2015) which found a reduction of 66 pmol/L (-65.8 (95% CI -78.1 to -53.6 pmol/L p<0.00001) for metformin use in an analysis of a more heterogeneous group of patients (including studies of specific groups of patients with hyperlipidaemia and polycystic ovarian syndrome) [8]. Our result is also similar to that of Liu et al (2014) [9], who found a reduction of 54 pmol/L in a meta-analysis, but included rosiglitazone as a control in the pooled estimate.…”

“…However, a systematic analysis of the data concerning B12 status and metformin usage has not been carried out to date specifically in patients with Type 2 Diabetes. Two recent meta-analyses [8,9] have shown a reduction in B12 levels in populations with metformin use but both used a mixed population of patient types (e.g. diabetes, polycystic ovary syndrome, hyperlipidaemia).…”

Use of Metformin for Cardiometabolic Risks in Psychiatric Practice: Need-to-Know Safety Issues

“…In this meta-analysis, 15 an examination of absolute B 12 levels from 22 studies (pooled N = 4,302) identified lower B 12 levels, by 65.8 (95% CI, 53.6-78.1) pmol/L, in association with metformin treatment; heterogeneity was high (I 2 = 98%), but the risk of publication bias was considered low. The result narrowly missed statistical significance when only RCT data (10 trials; pooled N = 897) were examined; B 12 levels were lower in the metformin group by 30.9 (95% CI, −3.7 to 66.7) pmol/L.…”

“…13,14 Metformin and Vitamin B 12 Metformin impairs the absorption of vitamin B 12 ; however, B 12 levels may be maintained in the normal range for months to years until the hepatic stores of the vitamin are depleted. Long-term treatment with metformin has been associated with clear evidence of low B 12 levels, and even of biochemical B 12 deficiency, as evident from the results of 2 meta-analyses, 15,16 presented below. Metformin: association with low B 12 levels.…”

“…The findings remained stable in different sensitivity analyses, including those based on sample size, study design, duration of metformin treatment, definition of B 12 deficiency, and other variables. 15 In a more restricted meta-analysis of RCTs that specifically provided change scores, Liu et al 16 It is illegal to post this copyrighted PDF on any website. 18 1.…”