What evidence is there to support monitoring a B12 level in patients who are taking metformin? How often should it be monitored?

Comment by InpharmD Researcher

Long-term use of metformin has been associated with vitamin B12 deficiency, with studies finding a significant decline in vitamin B12 levels among patients taking metformin for over 3 years. The ADA guidelines recommend periodic monitoring of vitamin B12 levels for patients on metformin, especially those who have been taking it for more than 4 years or have additional risk factors, as the risk of deficiency increases the longer someone takes metformin. However, a frequency for monitoring has not been agreed upon.

Background

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]

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 <100 mg. However, in patients taking multivitamins, vitamin B12 deficiency seems to occur less often (odds ratio 0.23; p<0.001) suggesting that supplementation may confer protection against deficiency. The contents of the multivitamins are not known but are believed to contain a vitamin B12 amount between 2 to 30 mcg/day. [3]

In a 2024 review article regarding vitamin B12 deficiency in patients taking metformin, recommendations regarding monitoring appear limited to regular monitoring via period assessments, without a clearly defined frequency. A cost-effective vitamin B12 deficiency screening criteria was provided by the authors (see Table 1) and should include asymptomatic patients as part of the evaluation. [4]

References:

[1] ElSayed NA, Aleppo G, Aroda VR, et al. 3. Prevention or delay of type 2 diabetes and associated comorbidities: standards of care in diabetes—2023. Diabetes Care. 2023;46(Supplement_1):S41-S48. doi:10.2337/dc23-S003
[2] Yang W, Cai X, Wu H, Ji L. Associations between metformin use and vitamin B12 levels, anemia, and neuropathy in patients with diabetes: a meta-analysis. J Diabetes. 2019;11(9):729-743. doi:10.1111/1753-0407.12900
[3] Kim J, Ahn CW, Fang S, Lee HS, Park JS. Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes. Medicine (Baltimore). 2019;98(46):e17918. doi:10.1097/MD.0000000000017918
[4] Ramzan NUH, Shahjahan K, Dhillon RA, et al. Vitamin B12 Deficiency in Patients Taking Metformin: Pathogenesis and Recommendations. Cureus. 2024;16(9):e68550. Published 2024 Sep 3. doi:10.7759/cureus.68550
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What evidence is there to support monitoring a B12 level in patients who are taking metformin? How often should it be monitored?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.


 

Screening criteria outlined for vitamin B12 deficiency
Screening number Screening criteria for vitamin B12 deficiency
1.

Strong clinical suspicion of deficiency, such as unexplained macrocytic anemia, and neurological symptoms, such as peripheral neuropathy, defined by abnormal monofilament examination, based on findings from the Diabetes Prevention Program/Diabetes Prevention Program Study
2.

In diabetic patients treated with metformin who already have peripheral and/or autonomic neuropathy due to diabetes
3.

Metformin treatment for five years or longer
4.

Elderly individuals aged 65 years and older
5.

High cumulative metformin exposure, indicated by an MUI value exceeding 5, applies to individuals diagnosed with type 2 diabetes who have been treated with metformin for a minimum of six months. The MUI is calculated as the daily metformin dose (in mg) multiplied by its duration (in years) and divided by 1,000

6.

A metformin dosage of 1,500 mg per day or more, maintained for at least six months, with the greatest risk of vitamin B12 deficiency noted at a daily metformin dose of 2,000 mg or higher
7.

Simultaneous prolonged use (≥12 months) of acid-suppressing medications such as PPIs and H2RAs
8.

Presence of comorbidities associated with increased risk of vitamin B12 deficiency warrants screening based on clinical judgment

MUI: metformin usage index; PPIs: proton pump inhibitors; H2RAs: H2 receptor antagonists
References:

Adapted from:
Ramzan NUH, Shahjahan K, Dhillon RA, et al. Vitamin B12 Deficiency in Patients Taking Metformin: Pathogenesis and Recommendations. Cureus. 2024;16(9):e68550. Published 2024 Sep 3. doi:10.7759/cureus.68550

 

Assessment of Vitamin B12 Deficiency and B12 Screening Trends for Patients on Metformin: A Retrospective Cohort Case Review

Design

Single-center, retrospective, observational, database analysis

N= 13,489

Objective

To investigate the use of vitamin B12 testing in a large cohort of patients on metformin and assess the benefit of formulating screening recommendations for vitamin B12 deficiency

Inclusion Criteria

Insured patients ≥18 years old who had more than 1 year of metformin use between 1 January 2010 and 1 October 2016; filled at least two consecutive prescriptions of metformin

Exclusion Criteria

History of vitamin B12 deficiency, a single prescription of metformin filled, first metformin prescription filled within 30 days of insurance

Methods

Data were collected via access to an administrative database of a non-profit health insurance plan offered by a large hospital system in Michigan. Age was categorized into quintiles (18-39 years old, 40-49 years old, 50-64 years old, 65-70 years old, and >80 years old). Subgroups of confounding variables included malabsorption syndromes and prescription proton pump inhibitor (PPI) use.

To be recommended for routine screening, vitamin B12 must meet certain criteria based on Wilson and Jungner's principles: (1) the disease is appropriate for screening; (2) screening is feasible and effective; and (3) the screening test is valid and widely available.

Duration

January 1, 2010 to December 31, 2018

Outcome Measures

Primary outcome: incidence of B12 deficiency diagnosed in patients on metformin

Secondary outcomes: occurrence of B12 testing in the patient population on metformin

Baseline Characteristics

  

Metformin (N= 13,489)

      

Age, years

18-39

40-49

50-64

65-79

>80

 

830 (6.2%)

1,716 (12.7%)

5,828 (43.2%)

4,196 (31.1%)

919 (6.8%)

      

Female

 7,242 (53.7%)      

Race

African-American

Caucasian

 

5,409 (40.1%)

5,858 (43.4%)

      

Confounders

Malabsorption disorders

PPI use

 

684 (5.1%)

3,957 (29.3%)

      

Results

 

Deficiency

Mean days to B12 deficiency

Ever tested

Mean days to test

All patients 

202/6,051 (3.3%)

1,926

6,051 (44.9%)

972

Age, years

18-39

40-49

50-64

65-79

>80 

 

3 (1.0%)

12 (2.1%)

64 (2.8%)

99 (4.3%)

24 (4.2%)

 

2,686

2,367

2,019

1,894

1,492 

 

292 (35.2%)

581 (33.9%)

2,316 (39.7%)

2,285 (54.5%)

577 (62.8%)

 

929

942

1,050

952

785

Gender

Male

Female

 

81 (3.1%)

121 (3.5%)

 

1,883

1,955

 

2,590 (41.5%)

3,461 (47.8%)

 

1,037

922

Malabsorption disorders

11 (2.2%)

 1,864 

498 (71.8%)

 860

PPI use

70 (3.2%)

 2,058

2,173 (54.9%)

 947 

African-American patients were less likely to be tested for B12 deficiency compared to other races (odds ratio [OR], 1.46; 95% CI, 1.402 to 1.514; p<0.001). Men were also less likely to be tested for vitamin B12 deficiency than women (p<0.05).

Patients with malabsorption disorders were more likely to be tested than the entire study population. Patients taking PPIs were also more likely to be tested for vitamin B12 deficiency; however, the deficiency rate was not statistically significant in these patients.

Of the 202 patients diagnosed with B12 deficiency, 105 charts were randomly reviewed to identify the most common reasons for vitamin B12 testing. Anaemia (26%), cognitive decline (17%), and neuropathy (16%) were the most commonly reported reasons, whereas only 3.8% stated that the B12 level was ordered for concern of deficiency caused by metformin.

Study Author Conclusions

These study findings suggest that physicians should be cognizant of the increased incidence of vitamin B12 deficiency in select populations. These populations include patients with greater than 5 years of metformin use and age greater than 65 years old. The patient’s race should also be considered.

InpharmD Researcher Critique

The study is unique as they distinguish the rates at which testing occurred and the rates at which populations were tested. In addition, the study is large and diverse, including more minorities other than just White patients. This study also accounted for confounders and excluded preexisting vitamin B12 deficiency. 

Limitations include not being able to address all potential confounders since this was an analysis of insurance claims. The study did not stratify patients based on metformin dosing or duration which may have also provided valuable information. This study was also an analysis of a single non-profit insurance plan in Michigan and the results may not apply to other areas.



References:

Martin D, Thaker J, Shreve M, Lamerato L, Budzynska K. Assessment of vitamin B12 deficiency and B12 screening trends for patients on metformin: a retrospective cohort case review. BMJ Nutr Prev Health. 2021;4(1):30-35. Published 2021 Jan 4. doi:10.1136/bmjnph-2020-000193

 

Evalution Of Vitamin B12 Monitoring In Patients On Metformin In Urban Ambulatory Care Settings

Design

Retrospective chart review

N= 322

Objective

To assess the occurrence of monitoring vitamin B12 levels in a diverse population

Study Groups

Vitamin B12 monitoring (n= 81)

No monitoring (n= 241)

Inclusion Criteria

Total daily metformin dose of ≥ 1000 mg for ≥ 6 months and a documented primary care provider visit during the year long study period

Exclusion Criteria

Diagnosis of type 1 diabetes, drug-induced diabetes, abnormal glucose elevations, prediabetes, polycystic ovarian syndrome, celiac disease, Crohn’s disease, Graves’ disease, chronic pancreatitis, alcoholism, human immunodeficiency virus (HIV), H.pylori infection, or pernicious anemia

Methods

Patient data was collected from six different ambulatory care sites focused on medically underserved populations. Patients were divided into those who had a vitamin B12 reading in the previous 5 years of index date versus those who did not.

Duration

January 1, 2017 to December 31, 2017

Primary Outcome

Primary: prevalence of normal (>350 pg/mL), low (200-350 pg/mL), and deficient (<200 pg/mL) vitamin B12 levels

Baseline Characteristics

  Patient Characteristics

Vitamin B12 monitoring (n= 81)

No monitoring (n= 241)

 p-value

Age, years

 69.23  56.42 <0.001

Female

 61.7% 54.8% 0.34

Race, n

White

African american

Hispanic

Asian/pacific islander

Other

Declined

 

56.8%

25.9%

9.9%

2.5%

1.2%

3.7%

 

37.8%

27.4%

19.5%

7.5%

2.9%

5.0%

0.004

Metformin daily dose

1000 mg to < 2000 mg

≥ 2000 mg

 

44.4%

55.6%

 

42.7%

57.3%

0.89

B12 supplementation

27.2%

4.6%

 <0.001

Results

Endpoint

Vitamin B12 monitoring (n= 81)

No monitoring (n= 241)

p-Value

Vitamin B12 monitoring

Normal levels

Low levels

Deficient levels

 

87.7%

11.1%

1.2%

 

--

  

Study Author Conclusions

In conclusion, the majority of patients at the FQHCs were not being monitored in accordance with the ADA guidelines. This revealed the need to educate providers and implement quality improvement projects to improve vitamin B12 monitoring in patients on chronic metformin therapy in ambulatory care settings. It would be beneficial for future studies to assess longitudinal vitamin B12 monitoring in order to better define the ideal frequency of vitamin B12 monitoring in patients with type 2 diabetes treated with metformin.

InpharmD Researcher Critique

The study primarily characterizes the patients who are likely to receive vitamin B12 monitoring and are less focused on the effect of metformin on vitamin B12 levels. A small sample size characterizing the Vitamin B12 monitoring group precludes analysis of metformin dose effect on vitamin B12 levels.



References:

Longo SL, Ryan JM, Sheehan KB, Reid DJ, Conley MP, Bouwmeester CJ. Evaluation of vitamin B12 monitoring in patients on metformin in urban ambulatory care settings. Pharm Pract (Granada). 2019 Jul-Sep;17(3):1499. doi: 10.18549/PharmPract.2019.3.1499. Epub 2019 Sep 13. PMID: 31592289; PMCID: PMC6763298.