Evaluation of Vitamin B 12 Monitoring in Veterans With Type 2 Diabetes on Metformin Therapy

Abstract

Background:

Studies have shown an association between metformin use and vitamin B₁₂ deficiency. Since 2017, the American Diabetes Association (ADA) Standards of Medical Care in Diabetes Guideline has included a recommendation for periodic vitamin B₁₂ measurements in metformin-treated patients, especially those with anemia or peripheral neuropathy.

Objective:

To determine the overall incidence and impact of the ADA Guideline on vitamin B₁₂ monitoring in a veteran population on long-term metformin therapy.

Methods:

Retrospective chart review was performed for patients on metformin who started therapy prior to 2005 at the VA North Texas Health Care System (VANTXHCS). The primary outcome was the proportion of patients with at least 1 vitamin B₁₂ level drawn during 2016 versus 2018. Metformin dose and duration, vitamin B₁₂ supplementation, and incident neuropathy prescriptions or diagnosis were also analyzed.

Results:

Of 394 patients included for the primary outcome, 136 (34.5%) had at least 1 vitamin B₁₂ level in 2016 versus 198 (50.3%) patients in 2018 (odds ratio: 1.94, P < .001). Of the 394 patients, 157 were diagnosed with neuropathy or prescribed a medication for neuropathy without a vitamin B₁₂ level in the previous year or with a low level that was not supplemented.

Conclusion:

Vitamin B₁₂ monitoring significantly increased between 2016 and 2018, aligning with the release of the 2017 ADA guidelines. However, a large proportion of patients were identified who were diagnosed with or treated for neuropathy without adequate vitamin B₁₂ monitoring.

Keywords

type 2 diabetes metformin

Introduction

Metformin is the recommended first-line therapy for the treatment of type 2 diabetes in patients with normal renal function and is widely used.^1–3 In the United States, 9.4% of the population has diabetes, a total of 30.3 million people.⁴ The prevalence among US veterans is even higher, 20.5%.⁵ Among US veterans with type 2 diabetes, almost 70% receive metformin.⁶ Considering its widespread use, the beneficial effects and potential harms of metformin have been extensively studied. Many studies have linked metformin to lowering of vitamin B₁₂ levels.^7–15 Despite this evidence, vitamin B₁₂ monitoring in patients treated with metformin is not routine and data are lacking regarding the clinical impact of monitoring vitamin B₁₂ levels.^8,16

Studies have shown that up to 30% of metformin-treated patients experience subnormal vitamin B₁₂ levels and up to 10% develop vitamin B₁₂ deficiency by laboratory assessment.^9,11,17–21 In these studies, the levels of vitamin B₁₂ have been 14% to 30% lower in patients taking metformin than in patients not taking metformin.^10,11,22 Longer duration of use and higher doses of metformin have been consistently associated with a greater risk for vitamin B₁₂ deficiency.^{11,13,18,20–22} One study found that each 1 mg/d increase in metformin dose was associated with a 0.042 pmol/L decrease in vitamin B₁₂ concentration.²⁰ Due to hepatic stores of vitamin B₁₂, it may take 5 to 15 years to develop absolute vitamin B₁₂ deficiency and for clinical symptoms to appear.^23,24 There is no standard value for vitamin B₁₂ deficiency or when to supplement patients; however, studies have utilized values ranging from <148 to <300 pg/mL.^9,17–20

Studies have found that metformin-treated patients with low vitamin B₁₂ levels have significantly more severe peripheral neuropathy than those with normal levels.^7,25 Since the consequences of vitamin B₁₂ deficiency can overlap with diabetic peripheral neuropathy, the diagnosis of vitamin B₁₂ deficiency could potentially be missed. If left untreated, this could lead to permanent neurological damage.²⁶ Low vitamin B₁₂ levels in patients on metformin have also been associated with depression and worse cognitive performance.²⁷

Current guidelines recommend monitoring vitamin B₁₂ levels in patients on long-term metformin therapy.^2,11,14 However, before January 2017, the American Diabetes Association (ADA) Guideline Standards of Medical Care in Diabetes did not include a recommendation to monitor vitamin B₁₂ for patients on metformin. In January 2017, the ADA released updated guidelines that included a new recommendation to consider periodic measurements of vitamin B₁₂ levels in patients treated with metformin, especially those with anemia or peripheral neuropathy.¹ The more recent versions of the guideline have continued to include this recommendation.^28,29 The guideline also recommends that, for all patients with diabetic peripheral neuropathy, alternative causes should be considered, including vitamin B₁₂ deficiency.¹ The objective of this study was to determine the overall incidence and impact of the ADA recommendation of periodic vitamin B₁₂ monitoring in metformin-treated patients.

Materials and Methods

Subjects

This retrospective cohort study was conducted at the VA North Texas Health Care System (VANTXHCS) and utilized the Computerized Patient Record System (CPRS) to access electronic medical records. Data were analyzed from time of metformin initiation through December 31, 2018, for each patient. Adult patients diagnosed with type 2 diabetes with an active metformin prescription who initiated metformin prior to 2005 were eligible for inclusion. Patients were excluded if they did not have regular Veterans Affairs (VA) follow-up (defined as less than 1 A1c in 2015) or if they were not consistently prescribed metformin throughout the study period (defined as less than 80% proportion of days covered). Additionally, patients were excluded for the subanalyses looking at metformin dose and duration if they had baseline anemia or vitamin B₁₂ deficiency or any documented medications or comorbidities throughout the study period that could impact vitamin B₁₂ levels (ie, proton pump inhibitors, histamine H₂-receptor antagonists, multivitamins, Helicobacter pylori infection, gastrointestinal surgery, Zollinger-Ellison syndrome, tropical sprue, celiac disease, or human immunodeficiency virus).

Study Variables

Demographic data collected include age, body mass index (BMI), gender, and race. Clinical data collected include metformin start date, incidence and dates of vitamin B₁₂ monitoring, resulting vitamin B₁₂ levels, and incident diagnoses and prescriptions. Data regarding medications and comorbidities that could impact vitamin B₁₂ levels were also collected. Incident diagnoses of anemia or neuropathy and corresponding prescriptions after starting metformin were searched for using the keywords anemia, neuropathy, gabapentin, pregabalin, duloxetine, venlafaxine, capsaicin, lidocaine, amitriptyline, nortriptyline, and tramadol in the patients’ charts. Both VA and non-VA records were analyzed, if documented. Using the same cohort of patients, data were compared between 2016 and 2018. The primary outcome was the proportion of patients with at least 1 vitamin B₁₂ level drawn during 2016 versus 2018. Secondary outcomes included analyzing the effect of metformin dose and duration on vitamin B₁₂ levels and to examine whether patients are being monitored and supplemented accordingly. An exploratory objective was developed to evaluate patients with incident diagnosis of neuropathy or new prescription medications for neuropathy after the initiation of metformin. Vitamin B₁₂ levels were categorized according to local lab reference ranges as sufficient (180-914 pg/mL), intermediate (145-179 pg/mL), or deficient (<145 pg/mL). If a patient had more than 1 vitamin B₁₂ level documented, the first level of that year was recorded. Vitamin B₁₂ levels as indications for supplementation were analyzed both according to local lab reference ranges and by current VANTXHCS practice (<250 pg/mL). To examine the effect of metformin dose on vitamin B₁₂ levels, doses were categorized as <1, 1 to 2, and >2 g/d. There were no specific guideline education or implementation strategies utilized at the VANTXHCS. There were also no automatic alerts in electronic medical records regarding screening for vitamin B₁₂ deficiency in long-term metformin users. The study protocol was reviewed and approved by the institutional review board.

Statistical Analysis

A McNemar test, adjusted for age, was performed on the primary outcome to compare the proportion of patients who received at least 1 vitamin B₁₂ level in 2016 versus 2018 after the ADA released new guidance on vitamin B₁₂ monitoring. It was estimated that 341 patients would be needed to provide 80% power in order to detect a 47% relative increase in the primary end point between 2016 and 2018 at a significance level of .05. Descriptive statistics were used for all other analyses.

Results

Patient Characteristics

A total of 420 patients who initiated metformin prior to 2005 were assessed for eligibility. Twenty-six patients were excluded due to having less than 1 A1c documented in 2015. The resulting 394 patients were included for the primary outcome (Figure 1). For the subanalyses looking at metformin dose and duration, 312 patients were further excluded. The most common reason for exclusion in the subanalysis was prescription of a PPI (119 patients) or cyanocobalamin (129 patients) during the study period. Of the 394 patients included, 381 (96.7%) were male, 263 (66.8%) were Caucasian, 81 (20.56%) were African American, and 4 (1.01%) were Hispanic. There were also 46 (11.67%) patients with undocumented race. The median age of patients included was 55 years (interquartile range [IQR]: 51-60) and the median BMI was 31.65 (IQR: 26.99-35.55).

Figure 1.

Patient screening for eligibility. Inclusion criteria included diagnosis of type 2 diabetes, age 18 or older, an active metformin prescription, and metformin initiation date prior to 2005. All patients assessed had at least 80% proportions of days covered (PDCs). Excluded medications for subanalyses were proton pump inhibitors, H2 antagonists, and multivitamins throughout the study period. Excluded comorbidities were Helicobacter pylori infection, gastrointestinal surgery, Zollinger-Ellison syndrome, tropical sprue, celiac disease, and HIV infection.

Outcomes

For the primary outcome (Figure 2), 136 (34.5%) patients had at least 1 vitamin B₁₂ level in 2016 versus 198 (50.3%) patients in 2018 (odds ratio: 1.94, P < .001) after adjusting for age. The average duration of metformin use during the study period was 16.33 years (range: 14.01-22.4 years). Of the 136 patients with documented vitamin B₁₂ levels in 2016, 3 levels were identified as deficient (1 supplemented, 2 not supplemented), 3 were intermediate, and 130 were sufficient. There were 20 levels identified in 2016 that were less than 250 pg/mL, of which 11 were supplemented with cyanocobalamin and 9 were not. Of the 198 patients with documented vitamin B₁₂ levels in 2018, 3 levels were identified as deficient (2 supplemented, 1 not supplemented), 14 were intermediate, and 181 were sufficient. There were 33 levels identified in 2018 that were less than 250 pg/mL, of which 19 were supplemented and 14 were not.

Figure 2.

Percentage of patients with at least 1 vitamin B₁₂ level drawn during the respective year.

Figure 3 depicts the number of vitamin B₁₂ levels drawn during the study period. Over the mean 16.33-year duration of metformin therapy during the study period, 55 (13.9%) patients were identified without any documented B₁₂ levels and 59 (14.97%) patients were identified with only 1 level. The results of the subanalyses evaluating the association of metformin dose and duration did not result in any significant trends (Figures 4 and 5).

Figure 3.

Number of vitamin B₁₂ levels during the study period (metformin start date through December 31, 2018).

Figure 4.

Association between metformin dose and vitamin B₁₂ levels.

Figure 5.

Association between metformin duration and vitamin B₁₂ levels.

Of the 394 patients included in the study, 117 patients were diagnosed with or prescribed medications for neuropathy without any documented vitamin B₁₂ levels since starting metformin. For 39 patients, it had been over 1 year since a B₁₂ level was documented when being diagnosed with or prescribed medications for neuropathy. One patient was also identified as having a vitamin B₁₂ level <250 pg/mL that was not supplemented and was subsequently prescribed a medication for neuropathy.

Discussion

The proportion of patients who received at least 1 vitamin B₁₂ level in 2018 was significantly higher than those in 2016. There was an overall increasing trend between 2016, 2017, and 2018. This aligns with the release of the ADA guidelines in January 2017 that introduced a new recommendation to periodically monitor vitamin B₁₂ levels for patients on long-term metformin therapy. However, the finding of 55 patients with no documented B₁₂ levels over an average 16.33 years of metformin use highlights opportunities for improvement.

The relatively low prevalence of vitamin B₁₂ monitoring found in this study is consistent with prior reports. Prior to the release of the 2017 ADA guidelines, Kancherla et al found that only 37% of older adults with diabetes on long-term metformin received vitamin B₁₂ monitoring.⁸ Pierce et al found that, in a veteran population taking at least 2 g of metformin per day for at least 1 year, 60% did not have vitamin B₁₂ measured.¹⁶ Of those who had been taking metformin for 10 years or more, 50% had never had vitamin B₁₂ tested.¹⁶ Less than 1% of subjects had an annual measurement of vitamin B₁₂ levels.¹⁶ Of subjects who had a new diagnosis of anemia or neuropathy during metformin therapy, 29% and 42% did not have a vitamin B₁₂ level measured, respectively.¹⁶

In addition, 23 of the 53 patients identified in this study with levels below 250 pg/mL did not receive supplementation with cyanocobalamin. The insufficient monitoring and supplementation of vitamin B₁₂ levels in this veteran population is concerning for multiple reasons. Untreated vitamin B₁₂ deficiency can lead to symptomatic anemia as well as neurologic manifestations including nerve function loss and gait abnormalities. These symptoms have the potential to be misinterpreted as diabetic peripheral neuropathy if vitamin B₁₂ levels are not appropriately monitored and addressed. After thorough review, this appears to have been a possibility in 39.8% of patients included in this study. However, since this was not the primary objective of this study, these results would need to be confirmed in future studies. The medications often used for diabetic peripheral neuropathy, such as gabapentin and tricyclic antidepressants, can increase central nervous system depression and fall risk, which is especially concerning in the mostly elderly veteran population. Therefore, these medications should be avoided when they are not indicated.

Strengths

To our knowledge, this is the first study to examine the impact of a guideline recommendation on vitamin B₁₂ monitoring in patients on long-term metformin therapy. All data were gathered through the VA CPRS system, which is a comprehensive database for prescriptions, lab results, diagnoses, and notes from all of the patient’s VA providers. Documented non-VA prescriptions were captured as well. Patients were on metformin for an average of 16.33 years during the study period, which is adequate time for vitamin B₁₂ deficiency and clinical symptoms to manifest. The study also included a sample size large enough to meet power requirements.

Limitations

The first limitation of this study is the relatively short amount of time after the release of the 2017 ADA guidelines to allow for implementation of recommendations. Studies have shown that it takes a median of 1 year for implementation of new policy statements and can take up to 10 years.³⁰ The second limitation regards the exclusion of patients prescribed cyanocobalamin during the study period for the subanalyses on metformin dose and duration. These patients were excluded because cyanocobalamin could influence resulting vitamin B₁₂ levels. However, excluding these patients also limits the studies’ ability to detect a decreasing trend in vitamin B₁₂ levels. This study was therefore unable to determine the effect of metformin dose and duration on vitamin B₁₂ levels. Another limitation is the unclear definition of “periodic monitoring” in the ADA guideline recommendation and no mention of a value for when to start supplementing vitamin B₁₂. A period of 1 year was chosen for monitoring parameters for this study per local expert opinion. Fourthly, serum vitamin B₁₂ measurement has poor sensitivity for reliable detection of B₁₂ deficiency. It is therefore recommended to use more than one biomarker to accurately diagnose vitamin B₁₂ deficiency, such as methylmalonic acid or holotranscobalamin.^31,32 Vitamin B₁₂ levels alone were chosen for this study as utilization of the other diagnostic methods was thought to be low. This study was performed as a retrospective chart review, and therefore, no causal effect can be determined. The results of the study have limited generalizability beyond the adult male veteran patient population.

Conclusion

This study demonstrated a statistically significant increase in vitamin B₁₂ monitoring after the release of the 2017 ADA Standards of Medical Care in Diabetes Guideline in a veteran population on metformin therapy. However, multiple patients were identified without any documented vitamin B₁₂ levels since starting metformin therapy. There were also a large number of patients who were diagnosed with neuropathy or prescribed a medication for neuropathy during the study period without adequate vitamin B₁₂ monitoring. Although an increase in vitamin B₁₂ monitoring was shown, greater awareness and compliance with monitoring would assist with preventing complications of vitamin B₁₂ deficiency and reducing the risk of patients being misdiagnosed with or mistreated for diabetic neuropathy.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Dr Alvarez receives funding from the National Institutes of Health (K08 DK101602).

ORCID iD

Haley A. Runeberg, PharmD, BCACP

References

American Diabetes Association. Standards of medical care in diabetes—2017. J Clin Appl Res Educ. 2017;40(suppl 1):S33–S43. doi:10.2337/dc17-S007.

Garber

Abrahamson

Barzilay

, et al. AACE/ACE Consensus Statement. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm—2016 executive summary. Endocr Pract. 2016;22(1):84–113. doi:10.4158/EP151126.CS.

Department of Veteran Affairs, Department of Defense. VA/DoD clinical practice guideline for the management of diabetes mellitus. Washington, DC: Department of Veteran Affairs, Department of Defense; 2010:146.

Center for Disease Control and Prevention. National Diabetes Statistics Report, 2017 Estimates of Diabetes and Its Burden in the United States Background. 2017. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed April 8, 2019.

Liu

Sayam

Shao

, et al. Prevalence of and trends in diabetes among veterans, United States, 2005-2014. Prev Chronic Dis. 2017;14:170230. doi:10.5888/pcd14.170230.

Wheeler

Moore

Forsberg

, et al. Mortality among veterans with type 2 diabetes initiating metformin, sulfonylurea or rosiglitazone monotherapy. Diabetologia. 2013;56(9):1934–1943. doi:10.1007/s00125-013-2958. -1.

Singh

Kumar

Karmakar

, et al. Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients. J Postgrad Med. 2013;59(4):253–257. doi:10.4103/0022-3859.123143.

Kancherla

Elliott

Patel

, et al. Long-term metformin therapy and monitoring for vitamin B12 deficiency among older veterans. J Am Geriatr Soc. 2017;65(5):1061–1066. doi:10.1111/jgs.14761.

GLUCOPHAGE®. 1995. https://packageinserts.bms.com/pi/pi_glucophage.pdf. Accessed April 8, 2019.

10.

de Jager

Kooy

Lehert

, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010;340:c2181. doi:10.1136/bmj.c2181.

11.

Aroda

Edelstein

Goldberg

, et al. Long-term metformin use and vitamin B12 deficiency in the diabetes prevention program outcomes study. J Clin Endocrinol Metab. 2016;101(4):1754–1761. doi:10.1210/jc.2015-3754.

12.

Pflipsen

Saguil

, et al. The prevalence of vitamin B12 deficiency in patients with type 2 diabetes: a cross-sectional study. J Am Board Fam Med. 2009;22(5):528–534. doi:10.3122/jabfm.2009.05.090044.

13.

Liu

Quan

, et al. Vitamin B12 status in metformin treated patients: systematic review. PLoS One. 2014;9(6):e100379. doi:10.1371/journal.pone.0100379.

14.

Chapman

Darling

Brown

. Association between metformin and vitamin B₁₂ deficiency in patients with type 2 diabetes: a systematic review and meta-analysis. Diabetes Metab. 2017;42(5):316–327. doi:10.1016/j.diabet.2016.03.008.

15.

Niafar

Hai

Porhomayon

, et al. The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med. 2015;10(1):93–102. doi:10.1007/s11739-014-1157-5.

16.

Pierce

Chung

Black

. Evaluation of vitamin B12 monitoring in a veteran population on long-term, high-dose metformin therapy. Ann Pharmacother. 2012;46(11):1470–1476. doi:10.1345/aph.1R223.

17.

Tomkin

Hadden

Weaver

, et al. Vitamin-B12 status of patients on long-term metformin therapy. Br Med J. 1971;2(5763):685–687. http://www.ncbi.nlm.nih.gov/pubmed/5556053. Accessed April 8, 2019.

18.

S-H

Ahn

Y-B

, et al. Association of vitamin B12 deficiency and metformin use in patients with type 2 diabetes. J Korean Med Sci. 2014;29(7):965–972. doi:10.3346/jkms.2014.29.7.965.

19.

Reinstatler

Williamson

, et al. Association of biochemical B 12 deficiency with metformin therapy and vitamin B 12 supplements: the national health and nutrition examination survey, 1999-2006. Diabetes Care. 2012;35(2):327–333. doi:10.2337/dc11-1582.

20.

Beulens

JWJ

Hart

Kuijs

, et al. Influence of duration and dose of metformin on cobalamin deficiency in type 2 diabetes patients using metformin. Acta Diabetol. 2015;52(1):47–53. doi:10.1007/s00592-014-0597-8.

21.

de Groot-Kamphuis

van Dijk

Groenier

, et al. Vitamin B12 deficiency and the lack of its consequences in type 2 diabetes patients using metformin. Neth J Med. 2013;71(7):386–390. http://www.ncbi.nlm.nih.gov/pubmed/24038568. Accessed April 8, 2019.

22.

Ting

Szeto

Chan

, et al. Risk factors of vitamin B 12 deficiency in patients receiving metformin. Arch Intern Med. 2006;166(18):1975–1979.

23.

Bell

DSH

. Metformin-induced vitamin B12 deficiency presenting as a peripheral neuropathy. South Med J. 2010;103(3):265–267. doi:10.1097/SMJ.0b013e3181ce0e4d.

24.

Langan

Zawistoski

. Update on vitamin B12 deficiency. Am Fam Physician. 2011;83(12):1425–1430.

25.

Wile

Toth

. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care. 2010;33(1):156–161. doi:10.2337/dc09-0606.

26.

Varela-Moreiras

Murphy

Scott

. Cobalamin, folic acid, and homocysteine. Nutr Rev. 2009;67(suppl 1):S69–S72. doi:10.1111/j.1753-4887.2009.00163.x.

27.

Biemans

Hart

Rutten

GEHM

, et al. Cobalamin status and its relation with depression, cognition and neuropathy in patients with type 2 diabetes mellitus using metformin. Acta Diabetol. 2014;52(2):383–393. doi:10.1007/s00592-014-0661-4.

28.

American Diabetes Association. Primary care—standards of medical care in diabetes. Diabetes Care. 2018;41(suppl 1):S1–S159. doi:10.2337/dc13-S011.

29.

American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care. 2019;42(suppl 1):S90–S102. doi:10.2337/dc19-S009.

30.

Hanney

Castle-Clarke

Grant

, et al. How long does biomedical research take? Studying the time taken between biomedical and health research and its translation into products, policy, and practice. Health Res Policy Syst. 2015;13(1):1. doi:10.1186/1478-4505-13. -1.

31.

Hughes

McNulty

. Assessing biomarker status of vitamin B12in the laboratory: no simple solution. Ann Clin Biochem. 2018;55(2):188–189. doi:10.1177/0004563217747907.

32.

Green

. Review article vitamin B 12 deficiency from the perspective of a practicing hematologist. Blood. 2018;129(19):2603–2611. doi:10.1182/blood-2016-10-569186.In.