EMBER Study: Metformin Use Linked to Vitamin B12 Deficiency


An analysis of data from more than 30,000 people with type 2 diabetes provides insight into the long-term use of metformin and risk of vitamin B12 deficiency.

Keri Hurley-Kim, PharmD, MPH | Credit: UC Irvine

Keri Hurley-Kim, PharmD, MPH
Credit: UC Irvine

Metformin use was associated with an increased risk of vitamin B12 deficiency, according to the results of a new study.

An analysis of data from people with type 2 diabetes within the National Institutes of Health’s All of Us research program, results of the EMBER study indicate using metformin for 4 or more years increased the risk of vitamin B12 deficiency by 41%, with each additional year of use increasing the risk of deficiency by 5%.1

“This adds to what is known from previously published trials and meta-analyses that indicate metformin-associated vitamin B12 deficiency is a time-dependent phenomenon that is hypothesized to be related to liver stores of vitamin B12 that take years to be depleted in most people,” wrote investigators.1 “This may also explain the lack of significant association between metformin use itself and deficiency.”

A cornerstone in the management of insulin resistance, data from the Medical Expenditure Panels Survey suggests an estimated 20 million people used metformin in the US during 2020, which would make it the third most commonly prescribed medication in the US behind only atorvastatin and levothyroxine. With such a high prevalence of use, knowledge of the long-term benefit-risk profile could impact the care for millions.2

Billed as the first study of its kind, the current research endeavor was conducted by Keri Hurley-Kim, PharmD, MPH, of UC Irvine, and colleagues with the intent of examining the relationship between metformin use and vitamin B12 deficiency using a large, real-world database. Using data from the All of Us research program, which includes data from more than 300,000 individuals, investigators identified 36,740 participants with type 2 for inclusion in the current study.1

A total of 6221 individuals with documented metformin use were identified among this cohort of 36,740 people with type 2 diabetes. The mean duration of use among the cohort of metformin users was 6.2 years. Relative to nonusers, metformin users had a greater mean age (65.3 years vs 60.1 years; P < .05), more Black or African American participants (28.9% vs 20.7%; P < .05) and Hispanic or Latino participants (20.1% vs 13.7%; P < 0.05), and had a higher proportion of males (38.4% vs 32.1%; P < .05).1

The primary outcome of interest for the investigators’ analyses was the incident of vitamin B12 deficiency, which was defined as fewer than 200 pg/mL. Investigators noted adjusted logistic regression models were used to estimate the association between metformin use and long-term use with risk of vitamin B12 deficiency. For the purpose of analysis, statistical models were adjusted for sociodemographic factors as well as self-reported overall health, vitamin B12 supplement use, years of metformin, vitamin B12 supplements, and proton pump inhibitor use.1

Upon analysis, vitamin B12 deficiency was present among 7.5% of metformin users and 6.3% of nonusers. Compared to nonusers with type 2 diabetes, metformin users with type 2 diabetes had a nonsignificant 5% greater risk of developing vitamin B12 deficiency (Odds Ratio [OR], 1.05, 95% Confidence Interval [CI], 0.93-1.18; P = .44).1

When assessing the influence of time, investigators found each additional year of metformin use was associated with an additional 5% increase in risk of deficiency (OR, 1.05; 95% CI, 1.03-1.08; P < .05). Investigators also pointed out long-term use of metformin, which was defined as 4 years or more, was associated with a 41% increase in risk relative to those using metformin for less than 4 years (OR, 1.41; 95% CI, 1.11-1.80; P < .05).1

Further analysis suggested use of metformin was associated with a statically significant increase in likelihood of experiencing a vitamin B12 borderline deficient results relative to nonusers (OR, 1.27; 95% CI, 1.20-1.35; P < .05). Additionally, results indicated each year of metformin use was associated with an increase in likelihood of a vitamin B12 borderline deficient result (OR, 1.02; 95% CI, 1.01-1.04; P < .05).1

“Future research should include further analysis of the time course of metformin-associated serum vitamin B12 reductions and deficiency, examination of the relationship between metformin-associated vitamin B12 deficiency and neuropathies, as well as evaluation for demographic disparities in screening, monitoring and treatment of low vitamin B12 levels in patients taking metformin,” investigators added.1


  1. Hurley-Kim K, Vu CH, Dao NM, et al. Effect of Metformin Use on Vitamin B12 Deficiency Over Time (EMBER): A Real-World Evidence Database Study [published online ahead of print, 2023 Aug 21]. Endocr Pract. 2023;S1530-891X(23)00526-8. doi:10.1016/j.eprac.2023.06.013
  2. Kane SP. Metformin. Metformin - Drug Usage Statistics, ClinCalc DrugStats Database. Accessed August 24, 2023. https://clincalc.com/DrugStats/Drugs/Metformin.
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