International Journal of General Medicine and Pharmacy (IJGMP) ISSN(P): 2319-3999; ISSN(E): 2319-4006 Vol. 4, Issue 1, Jan 2015, 53-60 © IASET
“VITAMIN B12 DEFICIENCY IN TYPE 2 DIABETES PATIENTS ON LONG TERM METFORMIN THERAPY FOR > 2YEARS” M. NARAYANASWAMY, NAGAPPA H. HANDARGAL & AKSHATHA M. Department of Medicine, Bangalore Medical College and Research Institute, Fort Road, Bangalore, India
ABSTRACT The number of subjects in the present study was 100 type 2 diabetic patients. All patients were more than 35 years and all were taking metformin therapy for > 2 years with different doses. Majority of patients were between the age group of 51-60 years. Total of 48 females and 52 males were considered for the study. The Vitamin B12 level status was assessed, in all of them by measuring serum Vitamin B12 levels. Total 24% of the patients had Vitamin B12 deficiency with age group 61-70 years when compared to non deficient patients (51-60 years). Age could be a risk factor for the development of Vitamin B12 levels. 91% of the patients were asymptomatic condition. FBS and PPBS were higher in the Vitamin B12 deficient people when compared to non deficient people with a mean of 227.38±22.92 and 317.04±31.1 and statistically significant p<0.01. The mean duration of diabetes was 12.33±3.55 years with HbA1c mean was 8.61±1.30 and found to be statistically significant p<0.01 when compared to non deficient patients. Most of the Vitamin B12 deficient patients (58.3%) were taking 1.5-2grams single dose orally metformin per day as compared with non deficient patients (98.7%) who were taking 500mg per day. 6% patients who were taking metformin 1gram per day have normal Vitamin B12 levels but on the lower side. All patients (4%) have been taking metformin sustained release and Vitamin B12 deficiency. Thus metformin sustained release will be cause the deficiency. Most of the Vitamin B12 deficient patients were taking metformin therapy for longer years (IQR 11-20 years) when compared to non deficient individuals taking for IQR 5-10 years with a mean of 12.33±3.55 years. Thus longer duration of metformin therapy causes more deficiency and found to be statistically significant p<0.001. Total 37% of patients who were taking metformin for comparatively lesser duration had normal Vitamin B12 levels but on the lower side. Out of 24 Vitamin B12 deficient patients 15 had levels between 190-210pg/ml and 2 patients had Vitamin B12 levels between 150-170pg/ml
KEYWORDS: Hba1c, Vitamin B12, Metformin, Asymptomatic INTRODUCTION Diabetes Mellitus (DM) comprises a common group of metabolic disorders that share the phenotype of hyperglycemias and are caused by complex interaction of genetics, environmental factors and life style choices. Based on etiopathogenic categories, it is classified as Type-1 and Type-2 diabetes mellitus. In Type-1 there is absolute deficiency of insulin secretion. In Type-2 there is a combination of resistance to insulin action and inadequate compensatory insulin secretor response Diabetes mellitus is accompanied by wide spread biochemical, morphological and functional abnormalities which may precipitate certain complications that affect the renal, cardio-vascular, neural systems and also skin, liver, collagen and elastic fibers. The incidence of Type 2 diabetes has been steadily increasing in urban areas to 8.4%. The rapid urbanization, change in the lifestyle coupled with ethnic susceptibility has increased the incidence of diabetes mellitus. This globally important condition needs to be understood with a proper perspective to deliver effective
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M. Narayanaswamy, Nagappa H. Handargal & Akshatha M
strategies to the individual and also the population. 2 This metabolic disorder is a risk factor precipitating micro vascular pathologies leading to autonomic neuropathy, nephropathy, retinopathy and peripheral neuropathy, and macro vascular pathologies leading to coronary artery disease, cerebrovascular accidents and peripheral vascular disease. us diabetes is a multisystem disorder that affects many organs of the body.1 The micro vascular complications appear early, within 5 to 10 years and macro vascular complications appear within 15 to 20yrs from the onset of diabetes 3. If diabetes is detected early and adequate steps are taken, it may be possible to significantly delay the occurrence of complications and thereafter the progression. The number of people with diabetes in world is expected to approximately double between 2000 and 2030 from 2.8% to 4.4% (171 million to 366 million). The greatest absolute increase in the number of people with diabetes will be in India. WHO estimates a projected rise to 80 million diabetics in India by 2030 from 32 million in 2000. Type 2 Diabetes mellitus accounts for 90-95% of all diabetics in India 4,5. The burden of the disease and its complications is increasing and hence there is greater need to recognize and manage the disease at earliest. India needs to implement the preventive measures to reduce the burden of diabetics as it poses a medical challenge, which is not matched by budget allocated for diabetes care in India. It is estimated that the annual cost of diabetes care were approximately Rs 90,200 million. The average expenditure per patient per year is about a minimum of Rs 4,500. Metformin is considered as a cornerstone in the treatment of diabetes and is the most frequently prescribed first line therapy for individuals with type 2 diabetes. In addition it is one of the few anti hyperglycemic agents associated with improvements in cardiovascular morbidity and mortality6.Vitamin B12- Intrinsic factor complex uptake by ileal cell surface receptors is known to be a process dependent on calcium availability. Metformin gives a positive charge to the surface of the membrane which acts to displace divalent cation like calcium. Impaired calcium availability due to metformin activity therefore interfere with calcium dependent process of vitamin B12 absorption. Hence intestinal absorption of Vitamin B12 is often decreased during chronic metformin therapy and calcium supplements reverse the effect of metformin on vitamin B12 absorption7-9. Decrease in vitamin B12 deficiency is a independent risk factor for cardiovascular disease, especially among individuals with type 2 diabetes. Vitamin B12 deficiency causes megaloblastic anaemia, peripheral neuropathy and subacute combined degeneration. Anaemia caused by Vitamin B12 deficiency is reversible; the progress of the neuropathy can at least be arrested as it cannot be reversed10-12. Both short term & long term use of metformin causes vitamin B12 deficiency but more pronounced with long term use. Normal blood levels of vitamin B12 is 211-900pg/ml. 10-30% of diabetic patients on long term treatment with metformin had vitamin B12 deficiency 13. The objective of this study is to find out the prevalence of vitamin B12 deficiency in type 2 diabetic patients on long term metformin therapy for >2yrs. Hence this study is been undertaken to know the VitaminB12 deficiency in Type 2 Diabetes patients on long term Metformin therapy for >2yrs.
MATERIALS AND METHODS A Patients visiting medicine OPD and patients who are admitted in IPD of Victoria and Bowring & Lady Curzon Hospital, BMCRI, Bangalore for the accrual the period of 1st January 2012 to 31st December 2012 were considered for the study. Total 100 patients recruited prospectively with written consent. All patients meet their inclusion and exclusion criteria. The secondary data was collected through pretested questionnaires. Type 2 diabetic subjects taking metformin therapy for >2yrs meeting the inclusion criteria of the study. Inclusion Criteria Patients with fasting blood glucose > 126mg/dl on two different occasions, postprandial > 200mg/dl. HbA1C Impact Factor (JCC): 2.9545
Index Copernicus Value (ICV): 3.0
â&#x20AC;&#x153;Vitamin B12 Deficiency in Type 2 Diabetes Patients on Long Term Metformin Therapy for > 2 yearsâ&#x20AC;?
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>6.5%, OGTT >200mg/dl. Type 2 Diabetic patients of age >18yrs. Type 2 Diabetic patients on intake of metformin for >2yrs Exclusion Criteria The patients who have not given written informed consent, Type 1 diabetes mellitus Diabetic complications. Intake of calcium, Malabsorption Syndrome, Intestinal infection
Partial/total gastrectomy, Patients on vitamin B12
supplements & Thyroid disorders Data was collected by using proforma meeting the objectives of the study. Purpose of the study was carefully explained to patients and consent was taken. All patients were interviewed, detailed history was taken with respect to risk factors and detailed physical examination was carried out and appropriate investigations were carried out Investigations After applying inclusion and exclusion criteria a randomly selected group of patients underwent detailed history, clinical examination and following set of investigations, Fasting blood glucose, postprandial blood glucose, HbA1C. Urine routine. Serum vitamin B12 levels, Complete blood picture with peripheral smear, Renal function test, serum electrolytes, Lipid profile. Thyroid function test , Stool for ova, cyst & occult blood , Chest X-ray, ECG & USG abdomen, Colonoscopy if required Protocol Type 2 diabetics were selected as per the criteria laid down. Their written consent was taken. The screening of diabetic subjects was done for exclusion criteria. The history was elicited. Age, duration of diabetes, duration of metformin therapy were recorded. Each subject was instructed to visit laboratory with 6 hrs of fasting on a specific date, the blood samples [3ml volume] was drawn for estimation of FBS and glycated hemoglobin. The fasting sample was also taken for serum Vitamin B12 level estimation. The subject was asked to take breakfast and blood sample was drawn 2 hrs later for PPBS estimation. The blood glucose parameters and glycated Hb levels, serum Vitamin B12 levels and other investigations were recorded in their respective proforma. The master chart containing this data of 100 type 2 diabetic patients was prepared
RESULT A total of 100 type 2 diabetic subjects were included in the present study, Among the 100 patients of study group highest number of cases were in age group of 51-60 years making 41% of the total. Least number of subjects belonged to age group of 71-80 years making about 1% of the total. Eldest and youngest age group was 75 and 38 respectively. Total 100 patients 52% were males and female comprises 48%. 91 cases were found to be asymptomatic forming and 9 cases were symptomatic. Among these 3 cases had viral fever, and burning micturition, 2 had easy fatigability (generalized weakness) 1 cases were notices trauma. Diabetes is found between 6-10 years with mean duration 20.0 years duration. 75% cases were taking metformin 500mg once in daily forming and 5% cases were taking metformin 500 mg for sustained release. Total 15% of patients single dose of metformin 500mg three with mean duration 6-10 years duration. 22 patients were noticed longer duration of metformin intake. The patients FBS is ranged from 126mg/dl - 300mg/dl. None of the patients were not noticed that FBS < 126mg/dl and also FBS between 200mg/dl to 300mg/dl forming 52% of the cases were found.
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M. Narayanaswamy, Nagappa H. Handargal & Akshatha M
The PPBS range between 150mg/dl - 400mg/dl. The highest 66.0% number of patients had PPBS between 201mg/dl - 300mg/dl. The Vitamin B12 levels in the study group ranged from 150-1300pg/ml.2% of the cases have found that Vitamin B12 levels in the study group were > 1000pgml and 61.0% low Vitamin B12 levels; 150-450pg/ml. The highest level was 1236 and the least was 159pg/ml. Most (61%) of the patients in the study group had Vitamin B12 levels on the upper side of lower limit. Present study noticed 24 had Vitamin B12 levels less than the normal value forming 24% and 76 patients who had normal Vitamin B12 levels and a total 37 had Vitamin B12 levels on the side of lower limits. 24 cases had Vitamin B12 deficiency. The mean of various clinical variables, age and duration of diabetes and duration of metformin intake were compared between the normal and Vitamin B12 patients. The concomitant variables like of age, duration of diabetes, duration of metformin intake, and mean of clinical variables like FBS, PPBS, HbA1c were found to be higher in Vitamin B12 deficiency when compared to normal patients and statistically significant (P <0.001). The maximum age distribution in Vitamin B12 deficiency patients was found between the age group 61-70 years. Higher in the age is statistically significantly p<0.05 with Vitamin B12 deficiency. Males as compared to female, the female patients had more Vitamin B12 deficiency and statistically significant p<0.05.The comparison of clinical features with normal and Vitamin B12 deficiency patients was done. Most of the patients were asymptomatic in both normal category forming 89.5% of the total and Vitamin B12 deficiency patients forming 95.8% of the total. Among symptoms both most of the normal patients and Vitamin B12 deficiency patients had hypertension forming 13.2% and 29.2% respectively. HbA1c levels < 7% forming (55.3%) of the total. Most of the Vitamin B12 deficiency type 2 diabetic patients had HbA1c levels between 7.1-8% (41.7%) and also found to be statistically significant P value <0.001. Vitamin B12 deficient patients had higher HbA1c >10 when compared to 3.9% of normal patients giving significant P value <0.001. Dose of metformin intake was compared between normal patients and Vitamin B12 deficiency patients. Most of the normal patients were taking metformin therapy 500mg once in daily (98.7%). The Vitamin B12 deficiency patients were taking metformin therapy 500mg three times daily forming 58.3% of the total. 58.3% Vitamin B12 deficiency patients were taking higher dose of metformin when compared to 1.3% of normal patients. Higher dose of metformin intake is significantly associated with Vitamin B12 deficiency with P value <0.001. The Duration of diabetes was compared between normal diabetes patients and Vitamin B12 deficiency diabetes patients. Most of the normal patients had diabetes between 6-10 years forming 48.7% of the total. Most of the Vitamin B12 deficiency had diabetes between 11-20 years forming 70.8% of the total. 70.8% Vitamin B12 deficiency patients were having diabetes for longer duration (11-20yrs) when compared to 6.6% of normal patients. Longer duration of diabetes is significantly associated with Vitamin B12 deficiency with P<0.001. Duration of metformin therapy was compared between normal patients and Vitamin B12 deficiency patients. Most of the normal patients were taking metformin between 6-10 years forming 48.7% of the total. Most of the Vitamin B12 deficiency was taking metformin between 11-20 years forming 70.8% of the total. 70.8% Vitamin B12 deficiency patients were taking metformin for longer duration when compared to 1.3% of normal patients. Longer duration of metformin intake is significantly associated with Vitamin B12 deficiency with P<0.001
DISCUSSIONS Present study was undertaken to assess Vitamin B12 deficiency in subjects with type2 diabetes mellitus taking long term metformin therapy for >2years. Larger population-based studies have been more consistent, demonstrating reduced Vitamin B12 levels in type 2 diabetic patients with metformin therapy. Metformin is considered as a cornerstone in the treatment of diabetes and is the most frequently prescribed first line therapy for individuals with type 2 diabetes. Absorption of Vitamin B12 is through the formation of Vitamin B12- Intrinsic factor complex uptake by ileal cell surface Impact Factor (JCC): 2.9545
Index Copernicus Value (ICV): 3.0
“Vitamin B12 Deficiency in Type 2 Diabetes Patients on Long Term Metformin Therapy for > 2 years”
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receptors. Metformin gives a positive charge to the surface of the membrane which acts to displace divalent cation and thus interferes with process of vitamin B12 absorption. Hence intestinal absorption of Vitamin B12 is often decreased during chronic metformin therapy. The prevalence of Vitamin B12 deficiency in various studies carried out previously in type 2 diabetes patients all over the world and the results of this study. Most of the previous studies like Pflipsen et al., total 60 cases have been compared the Vitamin B12 levels in diabetes patients, who are taking with or without metformin. The prevalence of Vitamin B12 deficiency was in the range of 15-30%. In the present study 24% of type 2 diabetes patients on metformin therapy were found to have Vitamin B12 less than normal. Few studies like Lael Reinstatler et al study have measured homocysteine and folate levels along with Vitamin B12 levels for better correlation. Almost all the studies shows low Vitamin B12 levels in diabetic patients taking metformin therapy. Out of the total 100 cases studied the number of male subjects was 52 and female subjects were 48. Males were higher in normal Vitamin B12 level group and females were comparatively higher in the deficient group. There was no significant difference found to be gender matched. None of the above studies showed any gender difference with Vitamin B12 deficiency. Largest number of patients belongs to the age group of 51 – 60 years. Patients with Vitamin B12 deficiency were found to be higher age group between 61-70 years with a mean of 61.92±6.04 compared to normal level individuals who were of age group between 51-60 years and it was statistical significant( P value <0.001). Monique Nervo et al 65 studied that type 2 diabetes patients who had low Vitamin B12 levels having higher age with the mean of 63.7+ 11.30. Jolien de Jager et al13 found that the age group of type 2 diabetes patients taking metformin in higher age group when compared to the patients not taking metformin therapy with a mean of 65.92±5.05 it is indicating that , the longer duration of metformin intake found to be statistically non significant. The duration of diabetes was higher in Vitamin B12 deficiency age group between 11-20 years with a mean of 12.33±3.55 when compared to non deficient group age group between 6-10 years and found to be statistically significant. Similar studies reported by others were not found to be statistical significance difference between the duration of diabetes and Vitamin B12 deficiency. Most of the B12 deficient patients were asymptomatic forming (95.8%) when compared to non deficient patients forming (89.5%). Pflipsen et al total 94% of metformin induced vitamin B12 deficient type 2 diabetic patients will be asymptomatic. FBS was high in deficient patients when compared to non deficient patients forming a mean of 227.38±22.92 when compared to non deficient (p<0.001). PPBS was high in deficient patients when compared to non deficient patients forming a mean of 317.04±31(p <0.001). Above studies were not showed any positive relation between lower Vitamin B12 levels and elevated FBS and PPBS levels. Though many patients had good control of HbA1c but the HbA1c was moderately higher in the deficiency group with a mean of 8.61±1.30 when compared to the normal group indicating (p< 0.001). Bauman et al reported in his study HbA1c was lower in the deficient group as they were not on metformin therapy and it would be control the HbA1c levels. Similar studies showed that the association between Vitamin B12 deficiency and HbA1c level were not showed any statistical significance differences p>0.05. The dose of metformin intake was higher in Vitamin B12 deficient groups (1500mg daily) when compared to non deficient individuals (500mg once daily) P <0.001. Raheel et al studied that ,the mean dose among B12 deficient patient was 2100 mg while in patients with normal B12 levels mean dose was 1582mg p>0.05. The dose of metformin had inversely related with B12 levels and the mean difference is found to be statistically significant p < 0.001. Ting et al ., studied that each 1g/d dose increment conferred a more than 2-fold increased risk of developing vitamin B12 deficiency with metformin with a significant P <0.001. The duration of metformin intake was higher in deficient group age group between 11-20 years with a mean of 12.33±3.55, when compared to non deficient age group between 5-10 years with a mean of 6.58±2.56 which were www.iaset.us
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statistically significant p <0.001. Raheel et al studied that mean B12 levels in patients on metformin for less than 24 months were 414 pg/ml (± 202) while those on more than 24 months was 188 pg/ml (± 78) with p <0.002. When comparing patients on metformin for less than 24 months with those on metformin for more than 24 months in B12 deficient patients results were found to be statistically significant with p <0.001. Pongchaidecha, Daryl wile and Leif sparre studied that metformin therapy given for 6months is sufficient to cause Vitamin B12 deficiency giving a statistically significant p<0.01 and the deficiency can be reversed by supplementing Vitamin B12 in early course of treatment.
CONCLUSIONS •
The present study has explored that, the relation between the metformin intake and Vitamin B12 deficiency in type 2 diabetes mellitus. This study has proved that age as well as the duration of diabetes increases the risk of developing Vitamin B12 deficiency in type 2 diabetes patients who are taking metformin therapy.
•
The study also showed that most of the patients were asymptomatic. This indicates that clinical manifestations of Vitamin B12 deficiency will take years later to manifest after depletion of Vitamin B12 levels in the body and hence measurement of Vitamin B12 levels is required in patients taking metformin therapy.
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Longer duration of diabetes is associated with longer duration of metformin intake and hence Vitamin B12 deficiency. This study has also showed that Vitamin B12 deficient type 2 diabetes patients on longer metformin therapy have higher FBS, PPBS and HbA1C levels
•
The higher dose of metformin intake has inverse relation with Vitamin B12 levels This study has proved that longer duration of metformin intake in type 2 diabetes patients causes Vitamin B12
deficiency. Hence type 2 diabetes patients taking long term metformin therapy should be screened for Vitamin B12 deficiency and should be supplemented with Vitamin B12
ACKNOWLEDGEMENTS The author acknowledge the Professor and Head, Dean BMCRI, Bangalore
REFERENCES 1.
Larsen, Kronenberg, Melmed, Polonsky, Williams textbook endocrinology.10th ed. Pennsylvinia: Elsevier India Publisher. 2003;10-15.
2.
Panner Selvam A. Gross hyperglycemia, domiciliary management in a rural set up. Manual of advanced Postgraduate course in Diabetology 1998; 18:170-175
3.
Benbassat Carlos A, Ervin Stern, Mordechai Kramer, Joseph Lebzelter, Ilana Blum, Gershon Fink. Pulmonary function in patients with Diabetes Mellitus. The Am J Med Sci 2001; 322(3):127-132
4.
Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care, 2004; 27:1047-1053
5.
Ramachandran A, Snehalatha C, Kapur A. Prevalence of diabetes by income in India. Diabetologia, 2001; 44(9): 1094-1101
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Index Copernicus Value (ICV): 3.0
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â&#x20AC;&#x153;Vitamin B12 Deficiency in Type 2 Diabetes Patients on Long Term Metformin Therapy for > 2 yearsâ&#x20AC;?
6.
Johnson JA, Simpson SH, Toth EL Majumdar SR. Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with Type 2 diabetes. Diabetes Med J. 2005; 22(4):497-502
7.
Davis Kibirige and Raymond Mwebaze. Vitamin B12 deficiency among patients with diabetes mellitus. J Diabetes Metab Disord. 2013; 12:17
8.
Adams JF, Clark JS, Ireland JT, Kesson CM, Watson WS. Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy. Diabetologia 1983; 24:16-18
9.
Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 2000; 23: 1227-31
10. Shihong Chen, Andrew J Lansdown, Stuart J Moat, Richard Ellis, Andrew Goringe, Frank DJ Dunstan, J Alan. Effect of Metformin on Vitamin B12 Status and Peripheral Neuropathy. J Neurol Sci. 1984; 66(1):117-26. 11. McCombe PA, McLeod JG. The peripheral neuropathy of vitamin B12 deficiency. J Neurol, 1988; 235(3):163-4.
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