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© JAPI • march 2012 • VOL. 60
Case Report
Metformin Associated B12 Deficiency
Anand Ajit Kumthekar*, Hitesh Vinod Gidwani**, Ajit Bhaskar Kumthekar***
Abstract
A
According to the ADA guidelines, metformin and lifestyle modifications are the first line therapies in the
treatment of type 2 diabetes mellitus. Metformin does, however, cause vitamin B-12 malabsorption, which may
increase the risk of developing vitamin B-12 deficiency — a clinically important and treatable condition. Here
we report a case of 60 year old diabetic male presenting with clinical features of Vitamin B-12 deficiency on long
term metformin therapy, which was confirmed on investigations. Patient showed symptomatic improvement
with change in treatment.
60 yr old male patient was brought to the OPD by his son
(who was abroad for 18 months) who noticed few changes
in the behaviour of his father like :
1.
Tendency to postpone intellectual work.
2.
Delay important business decisions and
3.
Slowness of higher functions.
On direct questioning the patient, said that he has been
having these complaints since last 2-3 months, felt lethargic and
experienced tingling numbness of both hands and feet, but he
did not report it to his physician. The symptoms were gradual
in onset and progressively worsened over a period of time and
were not noticed by his wife too. Dietary history revealed that he
was consuming a mixed diet with intake of meat at least 4 times
a week. The meat is usually chicken with occasional addition
of goat meat and rarely fish. Alcohol intake was once a week
in a quantity of 60-90ml. There is no history of smoking or any
other addictions. No history of alteration of bowel habits or any
abdominal surgery.
He is a known case of diabetes and hypertension for the last
5 years. He was on a regular therapy with Gliclazide (80mg)
and Metformin (850mg-1.5g) depending on his blood glucose
level control. Appropriate anti-hypertensive drugs were added
to control his hypertension.
O/E, Ht: 189cms, Wt: 119kg, BMI: 33.31. B.P was 140/100mm
and other vital parameters were normal. There was no pallor.
Significant findings in neurological examination were:
1.
Loss of sensations of touch and vibrations in both feet
2.
Ankle jerk was present bilaterally.
Cardiovascular, Respiratory and P/A examination were
normal.
Investigations
Laboratory data at initial visit revealed a haemoglobin of
12.1gm/dl and HbA1C of 8.5 %. Vibration Perception Threshold
(VPT) done with a Bio-Thesiometer demonstrated moderate
grade peripheral neuropathy in both lower limbs (Between
21-25 Volts). A B12 level was ordered which came back as 60pg/
ml (Normal=>140pg/ml). Patient was asked to discontinue
metformin, his anti-diabetic medications were adjusted for better
glycemic control and was given injectable B12 1 week apart
Resident Medical Officer, Sumati Diabetes Clinic, Nashik 422002;
Resident Medical Officer, Sunshine Diagnostic Centre, Mumbai
400050; ***Consultant Diabetologist, Sumati DiabetesClinic, Nashik
422002
Received: 07.05.2010; Revised: 27.09.2010; Accepted: 26.10.2010
*
**
for 4 weeks. B12 level after completion of injectable therapy
was 888.60pg/ml and VPT testing still demonstrated moderate
neuropathy. B12 level repeated after 8 months following
discontinuation of metformin therapy was 424.0 pg/ml and VPT
testing showed no neuropathy(< 15 volts), which was a marked
improvement (Table 1-5).
Management
Metformin was discontinued with immediate effect and he
was given hydroxycobalamine injections 1 week apart for 1
month. Patient was also advised to have liver soup in his diet.
After one month with this new treatment, he is feeling
better. His is more energetic and was prompt in taking business
decisions as he was before.
Tingling numbness has improved in both the legs. Serum
B12 level is 888pg/ml. Metformin was not reintroduced in the
management of diabetes. Gliclazide and voglibose were used
for glycemic control. Serum B12 levels assayed 8 months after
stopping metformin is 424 pg/ml.
Discussion
Metformin, a biguanide is an oral hypoglycaemic agent,
which has been in clinical practice for last 40 years. The UK
Prospective Diabetes Study Group 34 showed metformin to be
an effective hypoglycaemic agent with less weight gain, and
decreased hypoglycaemic episodes, myocardial infarction, stroke
and death. According to the new ADA/EASD guidelines, lifestyle
intervention and metformin are the first lines of treatment in the
management of hyperglycemia in type 2 DM.
Metformin use gives an excellent metabolic control and it
also has beneficial effects on the advanced glycation end product
formation in peripheral nerves and may prevent apoptosis
involved in diabetes-associated neurodegenerative processes.1,2
Metformin acts by decreasing the hepatic glucose output in
the fasting state. Initiation of metformin therapy can cause GI
disturbances, which can be reduced by starting low dose therapy
and gradually increasing. Lactic acidosis is rare if metformin is
used judiciously.
Metformin is also reported as a pharmacological cause of B12
deficiency. It is estimated that 10% to 30% of patients undergoing
metformin therapy develops evidence of vitamin B12 deficiency.3
Another study showed a 22% prevalence of B12 deficiency in
type 2 DM on metformin therapy.4
The responsible mechanism for B12 deficiency in metformin
users has been controversial; proposed contributors have
included competitive inhibition or inactivation of Cbl
© JAPI • march 2012 • VOL. 60 59
Table 4 : VPT (vibration sense of the foot) after 1month
injectable B12. Metformin was stopped.
Table 1 : Blood Investigations
Test
Hemoglobin
S.Creatinine
HbA1C
S.G.P.T
Observed Value
12.1 gm/dl
1.1 mg/dl
8.5 %
38.0
Table 2 : B12 Levels
Normal Value
11-15 gm/dl
0.8-1.4 mg/dl
<7%
35-45.0
Date
Current drug therapy Observed value Normal range
05/1/2010 Gliclazide + Metformin
< 60 pg/ml
>140 pg/ml
+ Ramipril
10/2/2010 Gliclazide + Ramipril
888.60 pg/ml
>140 pg/ml
+ injectable B12 1 week
apart for 1 month
19/9/2010 Gliclazide + Voglibose +
424.0 pg/ml
>140 pg/ml
Nevibolol + Prazosin +
Multivitamin tablet (Tab.
Eldervit)
Table 3 : VPT (Vibration Sense of the Foot by BioThesiometer) while on Metformin therapy
Average Reading
Below 15 volts
16-20 volts
21-25 volts
Above 25 volts
Inference
Right foot Left Foot
Normal
Mild Neuropathy
Moderate Neuropathy
√
√
Severe Neuropathy
absorption, alterations in intrinsic factor levels, bacterial flora,
gastrointestinal motility, and interaction with the cubulin
endocytic receptor. Patients on metformin have low B12 levels
because of a calcium dependent ileal membrane antagonism.
Low B12 levels due to prolonged metformin use can cause or
exacerbate diabetic peripheral neuropathy (DPN).5 Low serum
B12 levels also alter cerebral functions like memory, cognition,
alertness etc.
DPN is a common disorder and estimates show that 20% of
the adult diabetic population suffer from it.6 One important point
is that all cases of tingling numbness in a diabetic are not due to
DPN. Other causes (B12 deficiency, Hansen’s disease) should be
kept in mind. Currently there are no definitive guidelines for B12
level screening for patients on metformin but annual screening
may be worthwhile. Careful examination and appropriate
laboratory investigations can detect side effects associated with
Average Reading
Below 15 volts
16-20 volts
21-25 volts
Above 25 volts
Inference
Right foot Left Foot
Normal
Mild Neuropathy
Moderate Neuropathy
√
√
Severe Neuropathy
Table 5 : VPT (Vibration sense of the foot) 8 months after
stopping metformin
Average Reading
Below 15 volts
16-20 volts
21-25 volts
Above 25 volts
metformin use.
Inference
Right foot Left Foot
Normal
√
√
Mild Neuropathy
Moderate Neuropathy
Severe Neuropathy
References
1.
Tanaka Y, Uchino H, Shimizu T, Yoshii H, Niwa M, Ohmura
C,Mitsuhashi N, Onuma T, Kawamori R. Effect of metformin on
advanced glycation endproduct formation and peripheral nerve
function in streptozotocin-induced diabetic rats. Eur J Pharmacol
1999;376:17– 22
2.
El-Mir MY, Detaille D, R-Villanueva G, Delgado-Esteban M,Guigas
B, Attia S, Fontaine E, Almeida A, Leverve X. Neuroprotective role of
antidiabetic drug metformin against apoptotic cell death in primary
cortical neurons. J Mol Neurosci 2008;34:77– 87.
3.
Tomkin GH, Hadden DR, Weaver JA, Montgomery DA. VitaminB12 status of patients on long-term metformin therapy. BMJ
1971;2:685– 687.
4.
Matthew C. Pflipsen, Robert C. Oh, Aaron S, Dean A. Seehusen,
and Richard Topolski. The Prevalence of Vitamin B12 Deficiency in
Patients with Type 2 Diabetes: A Cross-Sectional Study. The Journal
of the American Board of Family Medicine 2009;22:528-534.
5.
Daryl J. Wile and Cory Toth. Association of Metformin, Elevated
Homocysteine, and Methylmalonic Acid Levels and Clinically
Worsened Diabetic Peripheral Neuropathy Diabetes Care January
2010;33:156-161.
6.
Andrew JM Boulton, Arthur I Vinik, Joseph C Arezzo,Vera Bril, Eva
L Feldman, Roy Freeman, Rayaz A Malik, Raelene E Maser, Jay M
Sosenko, Dan Ziegler. Diabetic Neuropathies A statement by the
American Diabetes Association. Diabetes Care 2005;28:956-962.