According to the American Diabetes Association (ADA) Standards of Care in Diabetes 2023 Guideline, long-term use of metformin can be associated with vitamin B12 deficiency. Although there isn’t a universally agreed-upon frequency for monitoring, it’s worth mentioning that the impact of metformin on vitamin B12 tends to amplify over time where one study observed a notably elevated risk of vitamin B12 deficiency (<150 pmol/L) at 4.3 years. The guidelines suggest that B12 levels should be measured periodically, with an emphasis on monitoring those who have anemia or peripheral neuropathy. They also suggest that those who have been on metformin for more than 4 years or have other risk factors for vitamin B12 deficiency have annual monitoring of B12 levels since the vitamin B12 lowering effect of metformin increases with time. The guidelines do not further delve into the definition of the long-term use or how long after stopping metformin the vitamin B12 levels are expected to normalize. [1]
A 2019 meta-analysis evaluated the associations between metformin use and serum vitamin B12 levels in order to potentially provide guidance on monitoring vitamin B12 levels in these patients. Of the 31 total studies, 23 (N= 5,227) provided information on the duration- and dose-dependent effects of metformin. As expected, patients taking metformin had significantly lower vitamin B12 levels than patients not taking metformin (p<0.00001). Subgroup analyses found this association occurred in patients taking metformin for <1 year (mean difference [MD] -28.94; 95% confidence interval [CI] -55.31 to -2.57 pmol/L; p= 0.03), between 1-3 years (MD -51.11; 95% CI -84.99 to -17.24 pmol/l ;p=0.003), and >3 years (MD -62.11; 95% CI -83.02 to -41.20 pmol/L; p<0.00001). Additionally, the magnitude of vitamin B12 decline increased as the duration of metformin therapy increased. Another subgroup analysis found significant decreases in vitamin B12 concentrations were associated with a mean metformin dose of <2,000 mg/day (MD -40.40; 95% CI -61.32 to -19.48 pmol/L; p=0.00002) as well as ≥2,000 mg/day (MD -66.06; 95% CI -86.32 to -45.80 pmol/L; p<0.00001). There was a greater reduction in serum vitamin B12 in patients taking ≥2,000 mg of metformin daily compared to <2,000 mg. Routine monitoring of vitamin B12 levels is suggested for patients taking metformin based on the available evidence, especially in patients >60 years of age and in patients who have been taking metformin for a long duration. The authors recommend annual monitoring of vitamin B12 levels in patients taking metformin to potentially avoid irreversible complications of vitamin B12 deficiency. [2]
A 2022 meta-analysis aimed to explore the effect of metformin use on vitamin B12 deficiency in patients with type 2 diabetes mellitus (T2DM). The study consisted of 17 studies, including 13 cross-sectional, 3 retrospective cohorts, and 1 case-control study. Significant factors linked to vitamin B12 deficiency in individuals with T2DM and using metformin included the duration of metformin use and a higher metformin dosage. Studies comparing the duration of metformin use showed notable differences between patients who used it for less than 4 years, those using it for 4-10 years, and those with more than 10 years of usage. The findings indicated a significant increase in the likelihood of vitamin B12 deficiency among patients who used metformin for 4-10 years (odds ratio [OR] 2.54, 95% CI 1.22 to 8.54, p= 0.001), and more than 10 years (OR 2.32, 95% CI 1.27 to 4.22, p= 0.001). In addition, individuals using a daily dosage of less than 1,000 mg are less prone to vitamin B12 deficiency compared to those taking 1,000 to 2,000 mg daily (OR 2.58, 95% CI 1.73 to 3.83, p= 0.001) and those with a daily dosage exceeding 2,000 mg (OR 5.89, 95% CI 2.63 to 13.19, p= 0.001). Overall, this study reveals a higher prevalence of vitamin B12 deficiency among patients receiving metformin compared to those not using metformin. Furthermore, factors associated with vitamin B12 deficiency in patients with T2DM and on metformin treatment include the daily metformin dosage and the duration of metformin use. The study did not explore the time it takes to reach a normal level of vitamin B12 after cessation of metformin. [3]
A 2021 review article discussed the association between long-term metformin therapy and vitamin B12 deficiency. It was suggested that metformin impairs vitamin B12 status primarily in a dose and duration-dependent manner. One study revealed that individuals with T2DM using metformin had a higher prevalence of vitamin B12 deficiency (14.1% vs. 4.4%) compared to non-users, with a metformin use duration of 4.9 years. Each 100 mg increase in metformin dose raised the odds of vitamin B12 deficiency by 8%. Another study in 550 T2DM patients using metformin found that higher daily and cumulative doses were strongly linked to lower holotranscobalamin (HoloTC) and cobalamin concentrations, but no association was found with the duration of metformin use. A nested case-control study suggested a more than 2-fold increased risk of vitamin B12 deficiency with each 1 g/d metformin dose increment, particularly in patients using metformin for 3 years or more (OR 2.39; 95% CI 1.46 to 3.91; p = 0.001). In another study involving 2,887 patients with T2DM, the combined effect of metformin dose and duration was assessed. They observed higher percentages of vitamin B12 deficiency (<200 pg/mL and 200-300 pg/mL) in metformin users compared to non-users. Using a metformin usage index (MUI), calculated as the product of daily dose and duration divided by 1,000, a significant association was found between MUI values >5 and a high risk of vitamin B12 deficiency. Adjusted regression analysis revealed the highest risk with MUI > 15, followed by MUI > 10, while the lowest risk was seen in patients with MUI <5. [4], [5], [6], [7]
While several studies indicate that the prevalence of B12 deficiency increases with the duration of metformin use, there is inconsistency in the findings regarding the specific duration required for vitamin B12 deficiency to occur in patients. The majority of studies propose that vitamin B12 deficiency associated with metformin use can manifest anywhere from 3 months to 5 years. Notably, one study observed B12 deficiency as early as 6 weeks into metformin use. [8], [9], [10], [11], [12], [13]
In a cross-sectional study of 1,111 patients with type 2 diabetes, doses of metformin at 1,500 mg/day or greater was associated with significantly greater decrease in vitamin B12 levels compared to metformin daily doses <1000 mg. However, in patients taking multivitamins, vitamin B12 deficiency seemed to occur less often (OR 0.23; p<0.001), suggesting that supplementation may confer protection against deficiency. In this study, the mean duration of metformin use was 10.1 ± 7.0 years (range of 0.5 to 45 years), with a mean daily dose of 1,339 ± 479 mg. Serum vitamin B12 levels demonstrated a negative correlation with metformin dose (r = −0.300, p <0 .001) with no significant correlation to the duration of metformin use (r = 0.030, p =0 .317). Categorizing daily metformin use dose (<1,000, 1,000-1,500, 1,500-2,000, and ≥2,000 mg) revealed a significant decrease in serum vitamin B12 levels as metformin dose increased (p<0.001). However, duration of metformin use categorized as <10, 10-20, and ≥20 years showed no significant correlation with serum vitamin B12 levels. [14]