Prevalence of vitamin B12
deficiency in Indian type 2 diabetes subjects on metformin therapy
Anil Kumar R.1,
Surekha
B. Shetty2, Lalitha R.3
1Dr R. Anil Kumar, Assistant Professor, 2Dr
Surekha B. Shetty,
Assistant Professor, 3Dr R Lalitha, Assistant
Professor, All authors are
affiliated to Karnataka Institute of Endocrinology and Research
Bangalore, Karnataka, India
Address for
Correspondence: Dr R. Anil Kumar, Email:
r.anil_kumar@yahoo.co.in
Abstract
Background:
To find out the prevalence of vitamin B12 deficiency in Indian type 2
diabetes subjects on metformin therapy. Material Methods: 161
type 2 diabetes subjects were studied over a period of 6 months at
Karnataka institute of endocrinology Bangalore. All subjects gave
written informed consent. BMI, Waist circumference, FPG, PPPG and HBA1c
were estimated. Vitamin B12 levels were estimated by
electrochemiluiminescence. We have excluded patients taking alcohol,
vitamin B12 supplements, pregnant woman, and type 1 diabetics. Subjects
whose vitamin B12 less than 200 picogram/ml were considered to be
deficient in vitamin B12. Subjects who were on metformin treatment for
more than 6 months were included in the study. Results: 118
diabetes subjects were males. They were in the age group of 30 to 80
years. Duration of diabetes was 1 to <5 years in 20.5%, 5 to
<10 years in 28.5% and 10 years and morein 51% of diabetes
subjects studied respectively. 55.9% of subjects had positive family
history of type 2 diabetes. 112 subjects were on 1000 mg metformin for
one year or more and 49 were on 2000 mg metformin for one year or more.
Prevalence of vitamin B12 deficiency was 27.33%. Conclusions: The
prevalence of vitamin B12 deficiency is 27.33% in type 2 diabetes
subjects on metformin therapy. The percentage of deficiency increased
with increase in dosage of metformin but there was no correlation to
duration of metformin therapy.
Keywords:
vitamin B12, Metformin, Type 2 diabetes
Manuscript received:
6th September 2017,
Reviewed:
15th September 2017
Author Corrected:
24th September 2017,
Accepted for Publication:
30th September 2017
Introduction
Vitamin B12 or cobalamin is a water-soluble vitamin that plays a very
fundamental role in DNA synthesis, optimal haemopoesis and neurological
function. The clinical picture of vitamin B12 deficiency hence, is
predominantly of features of haematological and neuro-cognitive
dysfunction [1].
The proposed mechanisms to explain metformin induced vitamin B12
deficiency among patients with T2DM include: alterations in small bowel
motility which stimulates bacterial overgrowth and consequential
vitamin B12 deficiency, competitive inhibition or inactivation of
vitamin B12 absorption, alterations in intrinsic factor (IF) levels and
interaction with the cubulin endocytic receptor[2]. Metformin has also
been shown to inhibit the calcium dependent absorption of the vitamin
B12-IF complex at the terminal ileum. This inhibitory effect is
reversed with calcium supplementation [3].
Decrease in vitamin B12 absorption and levels following metformin use
typically starts as early as the 4th month [4]. There is a large
storage of vitamin B12 in the liver so overt clinical features manifest
by 5 to 10 years [2].
Screening approach for vitamin B12 deficiency among patients with T2DM-
Currently, there are no published guidelines advocating for routine
screening for vitamin B12 deficiency among patients with T2DM. However,
among type 2 diabetic patients, it is clinically plausible to screen
for vitamin B12 deficiency prior to initiation of metformin and later
annually among elderly patients with history of long term use of
metformin ≥3-4 years, use of high doses of metformin (≥2
g/day), clinically worsening diabetic distal polyneuropathy in the
presence or absence of the haematological abnormalities [5].
The screening approach for vitamin B12 deficiency among diabetic
patients and the general population is similar. Measurement of the
serum vitamin B12 concentrations should be the preliminary screening
step for vitamin B12 deficiency among patients with T2DM.
Concentrations <200 pg/ml are usually diagnostic of vitamin B12
deficiency while concentrations >400 pg/ml confirm absence of
vitamin B12 deficiency [6].
Measurement of serum MMA or homocysteine concentrations is a more
sensitive and specific approach for screening especially among type 2
diabetic patients with borderline serum vitamin B12 concentrations of
200-400 pg/ml and subtle haematological manifestations. Serum
homocysteine and methylmalonic acid concentrations of 5-15
μmol/l and <0.28 μmol/l are considered within the
normal range respectively[5,7].
Reinstatler et al. in the National Health and Nutrition Examination
Survey of 1999–2006 in the USA defined Biochemical B12
deficiencyas serum levels ≤148 pmol/L, borderline deficiency as
serum B12 >148 to ≤221 pmol/L, and normal as >221
pmol/L(400 Pmol/L=550pg/ml [8].
Research methods-
Study design-161 type 2 diabetes subjects were studied over a period of
6 months at Karnataka institute of endocrinology and research
Bangalore.All subjects gave written informed consent. BMI, Waist
circumference, FPG, PPPG and HBA1c were estimated. Vitamin B12 levels
were estimated by electrochemiluiminescence.
Inclusion criteria-
Patients with type 2 diabetes, aged 30 to 80 yr, who had taken
metformin for at least six months were recruited at Karnataka institute
of endocrinology.
Exclusion criteria included patients with newly diagnosed type 2
diabetes, patients who had pernicious anemia, pregnant women, type 1
diabetes, decreased renal function (serum creatinine levels >
1.5 mg/dL for men and > 1.4 mg/dL for women), gastrectomy,
colectomy, inflammatory bowel disease, Patients were also excluded if
they had any severe medical illness, such as sepsis, severe infection,
malignancy, liver cirrhosis, heart failure, or renal failure patients
taking alcohol, vitamin B12 supplements.
Statistical methods-
Descriptive and inferential statistical analysis has been carried out
in the present study. Results on continuous measurements are presented
on Mean SD (Min-Max) and results on categorical measurements are
presented in Number (%). Significance is assessed at 5 % level of
significance. The following assumptions on data is made, Assumptions:
1.Dependent variables should be normally distributed, 2.Samples drawn
from the population should be random, Cases of the samples should be
independent Chi-square/ Fisher Exact test has been used to find the
significance of study parameters on categorical scale between two or
more groups.
In this study we have used values of
<200 pg/m/ml fordefinite vitamin B12 deficiency
>200 to 300 pg/ml for borderline vitamin B12 deficiency.
>300 pg/ml for normal vitamin B12 levels
Results-
118 diabetes subjects were males. They were in the age group of 30 to
80 years. Table 1
Table-1: Age distribution
of patients studied
|
Age in years
|
Gender
|
Total
|
|
Female
|
Male
|
|
<40
|
1(2.3%)
|
3(2.5%)
|
4(2.5%)
|
|
40-50
|
9(20.9%)
|
27(22.9%)
|
36(22.4%)
|
|
51-60
|
21(48.8%)
|
37(31.4%)
|
58(36%)
|
|
61-70
|
12(27.9%)
|
39(33.1%)
|
51(31.7%)
|
|
71-80
|
0(0%)
|
12(10.2%)
|
12(7.5%)
|
|
Total
|
43(100%)
|
118(100%)
|
161(100%)
|
BMI was less than 25 in 41% of patients, 25 to 30 in 44.7%
and more
than 30 in 14.3% of diabetes patients. Table 2
Table 2: BMI (kg/m2)
distribution of patients studied
|
BMI (kg/m2)
|
Gender
|
Total
|
|
Female
|
Male
|
|
<18.5
|
0(0%)
|
0(0%)
|
0(0%)
|
|
18.5-25
|
7(16.3%)
|
59(50%)
|
66(41%)
|
|
25-30
|
23(53.5%)
|
49(41.5%)
|
72(44.7%)
|
|
>30
|
13(30.2%)
|
10(8.5%)
|
23(14.3%)
|
|
Total
|
43(100%)
|
118(100%)
|
161(100%)
|
Duration of diabetes was 1 to <5 years in 26.1%, 5 to
<10
years in 34.8% and 10 years and morein 39.1% of diabetes subjects
studied respectively. 55.9% of subjects had positive family history of
type 2 diabetes.
Table -3: Vitamin B12 of
patients studied
|
Vitamin B12
|
Gender
|
Total
|
|
Female
|
Male
|
|
<200
|
9(20.9%)
|
35(29.7%)
|
44(27.3%)
|
|
200-300
|
9(20.9%)
|
34(28.8%)
|
43(26.7%)
|
|
>300
|
25(58.1%)
|
49(41.5%)
|
74(46%)
|
|
Total
|
43(100%)
|
118(100%)
|
161(100%)
|
Table- 4:
Metformin dose
of patients studied
|
Metformindose
|
Gender
|
Total
|
|
Female
|
Male
|
|
1000
|
34(79.1%)
|
78(66.1%)
|
112(69.6%)
|
|
2000
|
9(20.9%)
|
40(33.9%)
|
49(30.4%)
|
|
Total
|
43(100%)
|
118(100%)
|
161(100%)
|
Table-5:
Vitamin B12 in
relation to Metformin duration
|
Vitamin B12
|
Metfor min duration
|
Total
|
|
<5
|
5-10
|
>10
|
|
<200
|
27(33.3%)
|
10(21.3%)
|
7(21.2%)
|
44(27.3%)
|
|
200-300
|
20(24.7%)
|
13(27.7%)
|
10(30.3%)
|
43(26.7%)
|
|
>300
|
34(42%)
|
24(51.1%)
|
16(48.5%)
|
74(46%)
|
|
Total
|
81(100%)
|
47(100%)
|
33(100%)
|
161(100%)
|
112 subjects were on 1000 mg metformin for one year or more
and 49 were
on 2000 mg metformin for one year or more. Prevalence of vitamin B12
deficiency was 27.33%. Subgroup analysis showed that 23.2% on 1000 mg
metformin and 36.73% on 2000 mg metformin were deficient in vitamin B12
respectively. There was no correlation between vitamin B12 deficiency
and duration of metformin therapy. Table 3,4,5.
Discussion
According to ADA-EASD consensus, AACE, IDF and NICE guidelines
metformin is the first drug of choice in type 2 diabetes unless
contraindicated or not tolerated.Several cross-sectional studies [9,10]
and case reports [11,12] have documented an increased frequency of
vitamin B12 deficiency among type 2 DMpatients.Metformin use has been
unequivocally demonstrated as the prime factor associated with vitamin
B12 deficiency among patients with T2DM [13].Studies assessing type 2
diabetic patients on metformin have reported the prevalence of vitamin
B12 deficiency to range from 5.8% to 33% [8,13,14].This wide variation
in the reported prevalence could probably be explained by the varied
study definitions of vitamin B12 deficiency. In the cross sectional
study by Pflipsen et al. on 203 outpatient type 2 diabetic patients at
a large military primary care clinic in USA, definite vitamin B12
deficiency was defined as serum vitamin B12 concentrations of
<100 pg/ml or elevated serum methylmalonic acid of >243
nmol/L or homocysteine concentrations of >11.9 nmol/L if serum
vitamin B12 concentrations were between 100 to 350 pg/mL [8].In one
cross sectional study that documented a high prevalence of vitamin B12
deficiency of 33% among adult patients with T2DM by Qureshi et al.,
vitamin B12 deficiency was defined as serum vitamin B12 concentrations
<150 pg/ml [14], However, patients enrolled in this study were
those who were on high dose (>2 g/day) and long-term (4 years)
metformin treatment, both clinical factors known to be associated with
vitamin B12 deficiency.Due to the diverse definitions of vitamin B12
deficiency used in most studies and the cultural and religious beliefs
in different regions of the world, comparison of the prevalence of
vitamin B12 deficiency among T2DM patients and healthy general
populations is difficult.
In India, a country with a large proportion of vegetarians due to
cultural and religious beliefs, very high prevalence of vitamin B12
deficiency among the general population has been reported. In one study
by Yajnik et al. to determine the frequency of vitamin B12 deficiency
andhyperhomocysteinemia among 441 healthy middle aged Indian men,
vitamin B12 deficiency as defined by vitamin B12 concentrations
<150 pmol/L was reported among 67% of the study participants
[15].In another cross sectional study among 175 healthy elderly Indian
subjects aged >60 years, vitamin B12 deficiency also defined as
vitamin B12 concentrations <150 pmol/L was reported among 16% of
the study participants [16].In one early randomised controlled trial by
DeFronzo et al., metformin decreased the serum vitamin B12 levels by
22% and 29% compared to placebo and glyburide respectively[17].A
recent, randomized control trial designed to examine the temporal
relationship between metformin and serum B12 found a 19% reduction in
serum B12 levels compared with placebo after 4 years [18].Although
classical B12 deficiency presents with clinical symptoms such as
anaemia, peripheral neuropathy, depression, and cognitive impairment,
these symptoms are usually absent in those with biochemical B12
deficiency[19].
Vitamin B12 deficiency is clinically important because it is a
reversible cause of bone marrow failure and demyelinating nerve
disease. Neurologic damage, a possible consequence of metformin- induced
vitamin B12 deficiency, can present as peripheral neuropathy and may be
mistaken for diabetic neuropathy in patients on metformin treatment
[20].Low vitamin B12 levels have been reported to be associated with
worse nerve conduction velocities and poorer responses to light touch
by monofilament detection [21]. This may lead to the unnecessary use of
anticonvulsants or tricyclic antidepressants [20, 22, 23]. Another study
explored the relationship between low serum vitamin B12 levels and
cognitive impairment, depression and neuropathy. Low vitamin B12 states
were more associated with symptoms of memory impairment with objective
evidence of cognitive impairment than with depression or
neuropathy [24]. Prevalence of definite vitamin B12 deficiency in 27.3%
andbiochemical B12 deficiency in 26.3% is seen in the present study.
Subgroup analysis showed that 23.2% on 1000 mg metformin and 36.73% on
2000 mg metformin were deficient in vitamin B12 respectively. There was
no correlation between vitamin B12 deficiency and duration of metformin
therapy. As vitamin B12-associated neuropathy is a treatable and
reversible condition, early detection and treatment of vitamin B12
deficiency is clinically important in patients with diabetes using
metformin.
Conclusions
The prevalence of vitamin B12 deficiency is 27.33% in type 2 diabetes
subjects on metformin therapy. The percentage of deficiency increased
with increase in dosage of metformin but there was no correlation to
duration of metformin therapy. Clinically if the physicians suspect
vitamin B12 deficiency in type 2 diabetes subjects on metformin therapy
he should do vitamin B12 assay and accordingly treat with oral or
injection vitamin B12.
Acknowledgements-
Dr. K. P. Suresh, Scientist (Biostatistics), National Institute of
Animal Nutrition & Physiology, Bangalore-560030. No potential
conflicts of interest relevant to the article are reported.
Abbreviations
BMI- Body
mass index.Type2 DM- Type 2 diabetes mellitus.ADA-American
diabetes association.EASD-European association of study of
Diabetes.AACE-American association of college of
endocrinologyIDF-International diabetes federation
Funding:
Nil, Conflict of
interest: None initiated
Permission from IRB:
Yes
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How to cite this article?
Anil Kumar R, Surekha B. Shetty, Lalitha R. Prevalence of vitamin B12
deficiency in Indian type 2 diabetes subjects on metformin therapy. Int
J Med Res Rev 2017;5(09):845-850.doi:10.17511/ijmrr. 2017.i09.03.