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Pharmacists Letter / Prescribers Letter ~P.O. Box 8190, Stockton, CA 95208 ~Phone: 209-472-2240 ~Fax: 209-472-2249
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Detail-Document #250803
This Detail-Document accompanies the related article published in
PHARMACISTS LETTER / PRESCRIBERS LETTER
August 2009 ~Volume 25 ~Number 250803


Metformin-Induced Vitamin B12 Deficiency:
Can it Lead to Peripheral Neuropathy?

Introduction
Vitamin B12, or cyanocobalamin, is essential
for normal blood formation and neurological
function. Vitamin B12 is primarily obtained
through animal protein such as meat, eggs, and
dairy products, but it can also be found in fortified
foods such as breakfast cereal.
1,2
Deficiency of
vitamin B12 leads to anemia and neurological
damage. Metformin (Glucophage, others), a
medication commonly used in the treatment of
type 2 diabetes, has been associated with vitamin
B12 deficiency.
3
This document discusses the
role of metformin in vitamin B12 deficiency and
the resultant complications including peripheral
neuropathy.

Vitamin B12
The body stores a large amount of vitamin B12
and enterohepatic circulation is efficient, so it
often takes years for depletion of vitamin B12 and
the development of symptoms of deficiency.
Symptoms of mild vitamin B12 deficiency include
anemia, fatigue, weakness, shortness of breath,
and palpitations. Severe vitamin B12 deficiency
can result in neuropathy and peripheral nerve
damage, paresthesia, numbness, ataxia, abnormal
gait, memory loss, and dementia.
1,2,4
The
hematological signs of B12 deficiency are the
same as those seen with folate deficiency (i.e.,
increased mean corpuscular volume or MCV).
Differentiating between folate and vitamin B12
deficiencies is important in order to treat
effectively. In patients with vitamin B12
deficiency, folate supplementation may correct the
megaloblastic anemia, but will not treat the
neurologic deterioration. Appropriate treatment
of vitamin B12 deficiency is particularly
important in patients with diabetes, since
peripheral nerve damage due to B12 deficiency
could be confused with peripheral neuropathy due
to diabetes. Without early recognition and
treatment of B12 deficiency, permanent loss of
nerve function can result.
1,2,4

Cyanocobalamin is a cofactor in the
conversion of methylmalonyl-coenzyme A (CoA)
to succinyl-CoA. A deficiency of vitamin B12
can cause an increase in serum methylmalonyl-
CoA and its metabolic product, methylmalonic
acid (MMA). Cyanocobalamin is also a cofactor
in the synthesis of methionine from homocysteine.
Therefore, vitamin B12 deficiency can also lead to
an accumulation of homocysteine. Elevations of
both MMA and homocysteine are often noted in
patients with vitamin B12 deficiency.
1,2
The
clinical significance of this is not known.

Prevalence of Metformin-Induced B12
Deficiency
Metformin is commonly prescribed for the
treatment of type 2 diabetes. In general,
metformin therapy is well tolerated. One less well
recognized adverse effect of metformin is a
reduction in vitamin B12 levels. This effect is
mentioned in the package insert for Glucophage
and in clinical trials up to 29 weeks in duration, a
reduction of vitamin B12 levels from normal to
subnormal was seen in about 7% of patients.
3,5

However, other studies note that vitamin B12
malabsorption may occur in up to 30% of patients
treated long-term with metformin.
4,6
The
prescribing information also notes that this
adverse effect is rarely associated with anemia
and seems to be quickly reversible by stopping
metformin or starting vitamin B12
supplementation.
3

Case Reports and Clinical Trials
A number of case reports and small studies
demonstrate a relationship between metformin use
and vitamin B12 deficiency.
7
Gilligan and
colleagues report on a case of a 63 year-old male
who had taken metformin for at least five years.
Macrocytic anemia was noted and a Schilling test
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was performed. Results of the Schilling test were
suggestive of intestinal malabsorption of vitamin
B12. Following discontinuation of metformin,
and administration of vitamin B12 for two
months, a repeat Schilling test was normal.
In a report of 30 patients with metformin-
related vitamin B12 deficiency, Andres and
Federici found that the majority of cases of B12
deficiency were moderate with 90% of patients
demonstrating minor hematologic abnormalities
(median hemoglobin 11.5 g/dL, mean corpuscular
volume 95.4 fL) and only 30% reporting mild
peripheral neuropathy. However, two cases
demonstrated symptomatic anemia and
pancytopenia requiring blood transfusion.
8

A number of risk factors for metformin-
induced vitamin B12 deficiency exist. In a nested,
case-control study, 155 patients with diabetes who
were taking metformin and had vitamin B12
deficiency were compared with 310 patients with
diabetes who were taking metformin but did not
have vitamin B12 deficiency.
6
After adjusting for
confounders such as concurrent use of histamine-2
receptor antagonists or proton pump inhibitors,
vegetarian diet, and alcohol consumption, it was
found that there was a statistically significant
association between vitamin B12 deficiency and
metformin dose and duration of therapy. For each
one gram per day of metformin, the odds ratio of
developing vitamin B12 deficiency was 2.88
(95% confidence interval 2.15 to 3.87, p<0.001).
For those patients who used metformin therapy
for three years or more, the adjusted odds ratio of
developing vitamin B12 deficiency was 2.39
(95% confidence interval 1.46 to 3.91, p=0.001)
compared with those receiving metformin therapy
for less than three years. The authors suggested
that clinicians should have heightened vigilance
for vitamin B12 deficiency for patients who take
higher doses of metformin or in those who take
metformin for three or more years.
6

Overall, it is estimated that 10% to 30% of
patients taking metformin on a continuous basis
will develop evidence of reduced vitamin B12
absorption.
4,6,9,10
However, the consequences of
this deficiency are difficult to quantify.
Most recently, Braza and colleagues presented
information at the 2009 meeting of the American
Diabetes Association of a review of the
prevalence of vitamin B12 deficiency in Hispanic
patients with type 2 diabetes (n=76) taking
metformin. The average duration of metformin
therapy was 5 years. Of the patients who had
taken metformin for at least one year, 14 patients
(18.6%) were found to be vitamin B12 deficient,
and 17 patients (22.3%) had vitamin B12 levels in
the low-normal range. The authors found no
correlation between vitamin B12 deficiency and
mean corpuscular volume. But peripheral
neuropathy was noted in 7%, 23% and 77% of
those who had normal, low-normal and deficient
levels of vitamin B12 deficiency, respectively.
11

Mechanism of Metformin-Induced Vitamin
B12 Deficiency
The mechanism of metformin-induced vitamin
B12 deficiency is not known. Proposed
hypotheses include a disruption of absorption of
B12 in the ileum, or an inhibition of the calcium-
dependent uptake of the cyanocobalamin-intrinsic
factor complex by the intestines.
4,6,12
In fact, a
small preliminary study showed that
malabsorption of vitamin B12 in patients taking
metformin was reversed by oral calcium
supplementation.
4
In this study, 14 patients were
given metformin therapy for three months and
serum vitamin B12 levels and holotranscobalamin
were monitored monthly. Holotranscobalamin
levels fall when vitamin B12 absorption is
reduced, regardless of etiology. Serial serum
vitamin B12 and holotranscobalamin levels
declined over the metformin treatment period.
After three months, oral calcium carbonate
therapy, 1200 mg per day was administered for
one month. After one month of calcium carbonate
therapy, holotranscobalamin levels began to rise,
but serum vitamin B12 did not change
significantly compared with values prior to
calcium supplementation.
4


Recommendations
There are no formal clinical guidelines for the
management of patients with vitamin B12
deficiency associated with metformin use.
Management is geared towards identifying
patients at high risk for deficiency. Metformin
patients diagnosed with vitamin B12 deficiency
are treated similarly to patients with B12
deficiency due to other causes.
Patients with known risk factors for vitamin
B12 deficiency (i.e., vegetarian diet, chronic
alcohol ingestion, prolonged use of a histamine-2-
receptor antagonists or proton pump inhibitor)
(Detail-Document #250803: Page 3 of 4)
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www.pharmacistsletter.com ~www.prescribersletter.com
who are also taking metformin should be
monitored for signs and symptoms of
megaloblastic anemia.
6,12
Hematologic values
should be checked before starting metformin and
then periodically. The product information for
Glucophage recommends monitoring hematologic
parameters (hemoglobin, hematocrit, and red
blood cell indices) annually. In addition, in
patients at high-risk for deficiency, routine serum
vitamin B12 measurements at 2- to 3-year
intervals may be useful.
3,5
Many experts also
suggest checking vitamin B12 levels in
metformin-treated patients with anemia and in
those who develop or have worsening peripheral
neuropathy.
In patients with vitamin B12 deficiency,
treatment with oral vitamin B12 1000 mcg daily
should be initiated.
13
The daily requirement for
vitamin B12 is 1 to 2 mcg/day.
14
While it is
generally thought that intrinsic factor is necessary
for cyanocobalamin absorption, there is a pathway
that does not require intrinsic factor or the
presence of an intact ileum. Although it has not
been studied in patients with metformin-induced
vitamin B12 deficiency, it is known that if very
large doses of cyanocobalamin (1,000 to 10,000
mcg/day) are administered to patients with
pernicious anemia (i.e., patients without intrinsic
factor), approximately 1% of the dose is absorbed,
which meets the daily requirements.
13
Nasal
vitamin B12 preparations are not known to offer
therapeutic advantages over oral formulations and
are more expensive. Using injectable vitamin B12
preparations or discontinuing the metformin is
usually not necessary. In addition, normal daily
calcium ingestion through either food or
supplements should be encouraged because
calcium is important in vitamin B12 absorption.
4


Conclusion
Vitamin B12 deficiency due to metformin is a
less common, but potentially severe complication
that is often overlooked. Patients at risk for
vitamin B12 deficiency include those taking more
than 1,000 mg daily or those taking metformin for
three years or longer.
6
Patients receiving
metformin therapy should be monitored for signs
and symptoms of vitamin B12 deficiency such as
megaloblastic anemia or peripheral neuropathies
[Evidence level B; nonrandomized RCT].
4,6-9

Also, advise patients on metformin to take a
multivitamin with B12 and encourage them to get
their recommended daily amount of calcium,
although theres no proof this will prevent B12
deficiency.
While neuropathy can be related to
hyperglycemia, vitamin B12 deficiency should be
ruled out as a cause, especially in those patients
with diabetes who are taking metformin. In
patients with vitamin B12 deficiency,
supplemental oral vitamin B12 should be
administered.
13
Calcium supplementation to
assure that the recommended daily allowance is
being met can also be considered [Evidence level
B; nonrandomized RCT].
4



Users of this document are cautioned to use their own
professional judgment and consult any other necessary
or appropriate sources prior to making clinical
judgments based on the content of this document. Our
editors have researched the information with input
from experts, government agencies, and national
organizations. Information and Internet links in this
article were current as of the date of publication.

Levels of Evidence
In accordance with the trend towards Evidence-Based
Medicine, we are citing the LEVEL OF EVIDENCE
for the statements we publish.
Level Definition
A High-quality randomized controlled trial (RCT)
High-quality meta-analysis (quantitative
systematic review)
B Nonrandomized clinical trial
Nonquantitative systematic review
Lower quality RCT
Clinical cohort study
Case-control study
Historical control
Epidemiologic study
C Consensus
Expert opinion
D Anecdotal evidence
In vitro or animal study
Adapted from Siwek J , et al. How to write an evidence-based
clinical review article. Am Fam Physician 2002;65:251-8.

Project Leader in preparation of this Detail-
Document: Neeta Bahal OMara, Pharm.D.,
BCPS

References
1. Dharmarajan TS, Norkus EP. Approaches to
vitamin B12 deficiency. Early treatment may
prevent devastating complications. Postgrad Med
2001;110:99-105.
(Detail-Document #250803: Page 4 of 4)

2. Snow CF. Laboratory diagnosis of vitamin B12 and
folate deficiency. A guide for the primary care
physician. Arch Intern Med 1999;159:1289-1298.
3. Product information for metformin (Glucophage).
Bristol-Myers Squibb. Princeton, NJ 08543.
J anuary 2009.
4. Bauman WA, Shaw S, J ayatilleke E, et al.
Increased intake of calcium reverses vitamin B12
malabsorption induced by metformin. Diabetes
Care 2000;23:1227-31.
5. Product monograph for metformin (Glucophage).
Sanofi-Aventis Canada, Inc. Laval, Quebec H7L
4A8. April 2009.
6. Ting RZW, Szeto CC, Chan MHM, et al. Risk
factors of vitamin B12 deficiency in patients
receiving metformin. Arch Intern Med
2006;166:1975-79.
7. Gilligan MA. Metformin and vitamin B12 deficiency.
Arch Intern Med 2002;162:484-5.
8. Andres E, Federici L. Vitamin B12 deficiency in
patients receiving metformin: clinical data. Arch
Intern Med 2007;167:729. [letter]
9. Hermann LS, Nilsson BO, Wettre S. Vitamin B12
status of patients treated with metformin: a cross-
sectional cohort study. Br J Diabet Vasc Dis
2004;4:401-6.
10. Liu KW, Dai LK, J ean W. Metformin-related vitamin
B12 deficiency. Age Aging 2006;35:200-01.
11. Braza M, Hanley J , Bhatla A, Martinez M.
Relevance of vitamin B12 deficiency in Hispanic
patients with type 2 diabetes mellitus (DM) on long
term metformin Is it associated with peripheral
neuropathy? Presented at the American Diabetes
Association meeting, New Orleans, LA. J une 5-9,
2009. [Abstract 569-P].
12. Fitzgerald MA. Metformin-induced vitamin B12
deficiency. Nurse Pract 2007;32:6-7.
13. Kuzminski AM, DelGiacco EJ , Allen RH, et al.
Effective treatment of cobalamin deficiency with
oral cobalamin. Blood 1998;92:1191-8.
14. Dietary reference intakes for thiamine, riboflavin,
niacin, vitamin B6, folate, vitamin B12, pantothenic
acid, biotin, and choline (1998). Institute of
Medicine.
http://books.nap.edu/books/0309065542/html/306.h
tml. (Accessed J uly 14, 2009).







Cite this Detail-Document as follows: Metformin-induced vitamin B12 deficiency: can it lead to peripheral
neuropathy? Pharmacists Letter/Prescribers Letter 2009;25(8):250803.


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