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Metformin and Vitamin B12 Deficiency
Ala’a Abu Ghefreh, BPharm, PGCert, MSc
DRUG
INFORMATION
TEAM:
Nadine Halawa,
PharmD, BCPS, CGP
Mona Awadh,
BSc, PGCert, MSc
Ala’a Abu-Ghefreh,
BPharm, PGCert, MSc
Basil Dawwas,
BPharm, MPSA, MPSNZ
Heba Abduo,
BSc, BPharm, DipHM
Wadha Albader
MPharm
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Introduction
Vitamin B12, or cobalamin, is a water-soluble
vitamin that is naturally
found in some foods or
added to others. It is predominantly obtained
from animal products,
including fish, meat,
dairy products, poultry,
and eggs. It can also be
found in fortified foods
such as breakfast cereals.
Vitamin B12 is also
available as a dietary
supplement and a prescription medication.
Vitamin B12 is essential
for normal red blood cell
formation, neurological
function and DNA synthesis. The Recommended Dietary Allowance (RDA) of vitamin
B12 for adults is 2.4 micrograms per day.
In the stomach, hydrochloric acid and pepsin
release vitamin B12
from animal protein.
Free vitamin B12 then
binds to R proteins in
saliva and gastric juices.
In the duodenum, vitamin B12 is released
from R proteins by pancreatic proteases and
then binds to intrinsic
factor (IF), a glycoprotein secreted by the gastric parietal cells. However, vitamin B12 in fortified foods and dietary
supplements is already
in the free form, hence,
directly combines with
IF. B12- IF complex formation protects vitamin
B12 from being degraded by gastrointestinal microorganisms and
is also necessary for its
absorption. The B12- IF
complex binds to specific ileal receptors allowing vitamin B12 to
be absorbed.
Malabsorption of vitamin B12 can cause potentially irreversible
neurological damage and
life-threatening anemia.
The total body stores of
vitamin B12 are 20005000 micrograms, ap-
proximately 50% of
which are in the liver.
Therefore, it may take
several years to develop
symptoms of vitamin
B12 deficiency. Mild
symptoms include anemia, fatigue, weakness,
shortness of breath, and
palpitations. Whereas
severe vitamin B12 deficiency can cause neuropathy and peripheral
nerve damage, numbness,
paresthesia, ataxia, memory loss, abnormal gait,
dementia, and depression.
The neurological symptoms can appear without
anemia; therefore, early
diagnosis and management are essential to prevent irreversible neurological damage.
The hematological signs
of vitamin B12 deficiency are similar to
those seen with folate
deficiency. In patients
with vitamin B12 deficiency, folate supplementation may correct the
megaloblastic anemia, but not
the deterioration of neurologic
function. Without early detection and treatment, vitamin B12
deficiency can cause irreversible, clinically significant neuropathy. Therefore, differentiating between folate and vitamin
B12 deficiencies is essential to
assure effective management.
Early diagnosis and appropriate
treatment are particularly important in patients with Diabetes, as the clinical features of
peripheral nerve damage due to
vitamin B12 deficiency may be
confused with those of diabetic
peripheral neuropathy.
Metformin-associated Vitamin B12 Deficiency
Metformin is a commonly prescribed medication for the management of Type 2 Diabetes. A
number of studies demonstrated
that metformin therapy has been
associated with vitamin B12
deficiency. The mechanism of
metformin associated vitamin
B12 deficiency is not well understood. Metformin is thought
to induce vitamin B12 deficiency through interference with
the absorption of vitamin B12
and IF in the ileum, or inhibition of the calcium-dependent
uptake of the B12-IF complex
by the intestines, an effect that
may be reversed by calcium
supplementation.
In controlled clinical trials of
29 weeks duration, as stated in
the package insert of metformin (Glucophage®), a reduction of vitamin B12 levels
from normal to subnormal has
been observed in about 7% of
patients. This decrease is very
rarely associated with anemia
and appears to be readily reversible upon the discontinuation of metformin or the initiation of vitamin B12 substitutive therapy. A recent randomized placebo controlled trial
showed that the absolute risk
of vitamin B12 deficiency was
7.2 percentage points higher
with metformin compared to
placebo after a mean of 4.3
years of metformin therapy.
Moreover, this trial found that
the reduction in vitamin B12
concentration associated with
metformin increased with time.
Furthermore, another novel
finding in this study was that
the vitamin B12 concentrations
in some patients dropped to the
level at which most authorities
agree substitution is necessary.
Based on these findings, the
authors recommended that routine assessment of vitamin B12
levels during long-term treatment with metformin should be
strongly considered. On the
other hand, some studies noted
that vitamin B12 malabsorption may affect up to 30% of
patients on long-term metformin treatment. Furthermore,
a high percentage of vitamin
B12 deficiency has been observed in diabetic patients with
peripheral neuropathy on high
dose metformin therapy.
Identification of risk factors for
metformin-associated vitamin
B12 deficiency is crucial for
planning screening and prevention strategies in metformin
treated patients. In a nested case
-control study, 155 patients with
Diabetes and vitamin B12 deficiency due to metformin treatment were compared with 310
matched controls who were taking metformin but did not have
vitamin B12 deficiency. After
adjusting for potential confounders (such as concurrent
histamine-2 receptor antagonists
or proton pump inhibitors, vegetarian diet, and chronic alcohol
consumption), a clinically important and statistically significant association of vitamin B12
deficiency with dose and duration of metformin therapy has
been found. For each one gram
per day of metformin, the odds
ratio for developing vitamin
B12 deficiency was 2.88 (95%
confidence interval, 2.15-3.87)
(p<0.001). The adjusted odds
ratio of developing vitamin B12
deficiency among patients taking metformin for three years or
more was 2.39 (95% confidence
interval, 1.46-3.91) (p=0.001)
compared with those receiving
metformin for less than three
years. Therefore, the authors
suggested that these findings
reinforce the need for monitoring of at-risk patients receiving
high-dose and/or long-term metformin therapy.
Although there is no formal
clinical guidelines for the
treatment of vitamin B12 deficiency associated with metformin use, clinicians should
be aware of the importance of
early detection and treatment
of vitamin B12 deficiency.
Studies have shown that some
symptoms of vitamin B12 deficiency such as peripheral
neuropathies are hard to diagnose and can be irreversible.
Recovery of neurological
symptoms may be observed
within six months of vitamin
B12 substitutive therapy.
However, if there is no recovery after adequate treatment,
the neuropathy is most likely
to be irreversible at this stage.
Monitoring for signs and
symptoms of megaloblastic
anemia should be strongly
considered in patients at risk
for vitamin B12 deficiency
who are also receiving metformin. The product information of metformin recommends monitoring of hematologic parameters on an annual basis. In addition, any
abnormalities should be properly investigated and managed. Furthermore, routine
assessment of serum vitamin
B12 at 2- to 3- year intervals
may be useful in patients predisposed to developing vitamin B12 deficiency such as
those with inadequate vitamin
B12 or calcium intake or absorption. Many experts suggest that all patients with Type
2 Diabetes on long-term treat-
ment with high dose metformin
(i.e. more than 1,000 mg daily)
should be assessed for vitamin
B12 deficiency, especially if
complicated by peripheral neuropathy. Management of metformin-associated vitamin B12
deficiency should be geared towards identifying patients at
high risk for developing this
chronic complication. Patients
on metformin may be advised
to take a multivitamin containing vitamin B12 and to ensure
they get their recommended
daily requirement of calcium,
although there is no evidence
this will prevent vitamin B12
deficiency. In patients with vitamin B12 deficiency, vitamin
B12 substitutive therapy should
be initiated. In addition, calcium supplementation to suffice
the recommended daily allowance may also be considered in
these patients.
Conclusions
Metformin-associated malabsorption of vitamin B12 is a
chronic complication that may
affect up to 30% of patients
with Diabetes on long-term
high dose metformin therapy.
Vitamin B12 deficiency is often
overlooked and untreated. The
effect of metformin on vitamin
B12 levels may increase overtime and some vitamin B12 deficiency symptoms can be irreversible. Therefore, routine as-
sessment is warranted in patients taking high dose metformin, or those taking the
drug for three years or longer.
Patients should be monitored
for signs and symptoms of vitamin B12 deficiency, including megaloblastic anemia or
peripheral neuropathy. Although neuropathy can be
linked to hyperglycemia, vitamin B12 deficiency must be
ruled out as a cause, especially
in patients with diabetes on
metformin therapy. Metformin-treated patients who
are diagnosed with vitamin
B12 deficiency should receive
supplemental vitamin B12,
and possibly a calcium supplement to ensure the recommended daily allowance is being met.
References
1. de Jager J, Kooy A, Lehert P 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:c218
2. NIH Office of Dietary Supplements. Dietary Supplement Fact Sheet: Vitamin B12. http://
ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional/. Reviewed June 24, 2011. Accessed September
12, 2012.
3. O’Mara, N. B. Metformin-induced vitamin B12 Deficiency: can it lead to peripheral neuropathy?
Pharmacist’s Letter 2009 August. Detail No.: 250803 [Electronic version]. Available at: http://
www.pharmacistsletter.com. Accessed September 12, 2012.
4. Product information for Glucophage. Bristol-Myers Squibb Company. Princeton, NJ 08543 USA.
January 2009.
5. Qureshi SA, Ainsworth A, Winocour PH. Metformin therapy and assessment for vitamin B12 deficiency: is it necessary? Practical Diabetes 2011; 28(7): 302-304.
6. Schrier SL. Etiology and clinical manifestations of vitamin B12 and folic acid deficiency. UpToDate
Website. http://www.uptodate.com/contents/etiology-and-clinical-manifestations-of-vitamin-b12-and-folicacid-deficiency?source=search_result&search=etiology+and+manifestations+of+vitamin +B12+and+ folic+ acid+
deficiency&selectedTitle=1~150. Updated September 6, 2012. Accessed September 17, 2012.
7. Shaver K. Metformin and vitamin B12 deficiency. Pharmacist’s Letter 2002 April. Detail No.: 180403
[Electronic version]. Available at: http://www.pharmacistsletter.com. Accessed September 12, 2012.
8. Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM. Risk factors of vitamin B12 deficiency in patients
receiving metformin. Arch Intern Med. 2006; 166(18):1975-1979.
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