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Revista da Associação Médica Brasileira

Print version ISSN 0104-4230

Rev. Assoc. Med. Bras. vol.57 no.1 São Paulo Jan./Feb. 2011

http://dx.doi.org/10.1590/S0104-42302011000100015 

ARTIGO ORIGINAL

 

Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil

 

Vitamina B12 em pacientes diabéticos usando metformina: um corte transversal no Brasil

 

 

Monique NervoI; Adriano LubiniI; Fabiana Viegas RaimundoII; Gustavo Adolpho Moreira FaulhaberIII; Carine LeiteI; Leonardo Moura FischerI; Tania Weber FurlanettoIV

IM.D., Internal Medicine Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS
IINutritionist, Master's Degree Student, Postgraduation Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul - UFRGS, Porto Alegre, RS
IIIM.D., PhD, Internal Medicine Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS
IVM.D., PhD, Associate Professor, UFRGS, Internal Medicine Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS

Correspondence to

 

 


SUMMARY

OBJECTIVE: The objective of this study was to evaluate the presence of vitamin B12 deficiency and the factors associated with serum vitamin B12 levels in a sample of metformin-treated Brazilian diabetic patients.
METHOD: Cross-sectional study.
RESULTS: 144 patients were included. Serum vitamin B12 levels were low (< 125 pmol/L) in 10 patients (6.9%) and possibly low (125 - 250 pmol/L) in 53 patients (36.8%). Serum vitamin B12 levels were negatively associated with age (B = -3.17;
β= -0.171; p = 0.037) and duration of metformin use (B= -33.36; β= -0.161; p = 0.048), and positively associated with the estimated intake of vitamin B12 (B= 67.96; β= 0.249; p = 0.002).
CONCLUSION: The present findings suggest a high prevalence of vitamin B12 deficiency in metformin-treated diabetic patients. Older patients, patients in long term treatment with metformin and low vitamin B12 intake are probably more prone to this deficiency.

Keywords: Diabetes mellitus; vitamin B 12; metformin.


RESUMO

OBJETIVO: O objetivo deste estudo foi avaliar a prevalência de deficiência de vitamina B12 em pacientes diabéticos brasileiros tratados com metformina e os fatores associados aos níveis séricos de vitamina B12.
MÉTODO: Corte transversal.
RESULTADOS: 144 pacientes foram incluídos. Os níveis séricos de vitamina B12 foram baixos (< 125 pmol/L) em 10 pacientes (6,9%) e possivelmente baixos (125 - 250pmol/L) em 53 pacientes (36,8%). Os níveis séricos de vitamina B12 foram associados negativamente à idade (B = -3,17;
β = -0,171; p = 0,037) e à duração do uso de metformina (B = -33,36; β= -0,161; p = 0,048) e positivamente com a ingestão estimada de vitamina B12 (B = 67,96; β = 0,249; p = 0,002).
CONCLUSÃO: Estes resultados sugerem alta prevalência de deficiência de vitamina B12 em pacientes diabéticos tratados com metformina. Pacientes mais velhos, em uso de metformina há muito tempo e com ingestão baixa de vitamina B12 estão provavelmente mais predispostos a essa deficiência.

Unitermos: Diabetes mellitus; vitamina B 12; metformina.


 

 

Introduction

Vitamin B12 deficiency can lead to hematological abnormalities, cognitive disorders, and neuropathy1. This vitamin is obtained from animal origin food, so its deficiency may be related to eating habits, changes in the absorption or metabolic mechanisms.

Metformin is the first choice of treatment for type 2 diabetes mellitus (DM2), decreasing insulin resistance, and cardiovascular and mortality risks. It is usually well tolerated, although it may cause gastrointestinal side-effects2.

The association of metformin with vitamin B12 deficiency has been studied for some time, yet, the mechanism leading to this deficiency is not fully understood3,4. Recently, vitamin B12 deficiency has been associated with neuropathy in metformin-treated diabetic patients5.

A literature review was made in the PubMed and LILACS databases combining the keywords: vitamin B12 and metformin and no studies with Brazilian patients were identified until August, 2010. Given the importance of vitamin B12 deficiency, this study aimed to estimate its prevalence and to evaluate factors associated with serum vitamin B12 levels in metformin-treated DM2 patients, in the outpatient setting of a tertiary hospital in Southern Brazil.

 

Methods

All DM2 patients treated with metformin for more than one year in the ambulatory of Internal Medicine at the Hospital de Clinicas of Porto Alegre were invited to participate, until completion of the sample. Patients with partial or total gastrectomy, Crohn's disease, disorders of the terminal ileum and using supplemental vitamin B12 were excluded. Factors evaluated in the study were age, gender, weight, metformin dosage, duration of metformin use, dietary intake of vitamin B12, red cell mean corpuscular volume (MCV), glycosylated hemoglobin and use of other medications or supplements.

Sample size was set to 147 patients estimating a 25% prevalence of vitamin B12 deficiency, with an accuracy of 7%, and p < 0.05.

Intake of vitamin B12 was estimated by the 24-hour food recall method. The book Álbum fotográfico de porções alimentares. (Photographic Record for Dietary Inquiries): appliances and parts was used to illustrate the food portions6. A table was used to convert approximate cooking measurements into grams 7. Based on this information, intake of vitamin B12 was estimated using a chart containing the amount of vitamin B12 in food in Brazil8. Vitamin B12 intake was considered adequate or not according to the Dietary Reference Intake (DRI) for vitamin B12, as proposed by the Institute of Medicine of the USA9.

This study was approved by the Ethics Committee on Research of the Hospital de Clinicas de Porto Alegre and all patients signed an informed consent before entering the study. One blood sample from each patient was obtained and serum samples were stored at - 70ºC. Vitamin B12 levels were determined in a single batch by electrochemiluminescence - Modular E170 Roche. Vitamin B12 deficiency was defined by a serum level < 125 pmol/L and was considered possible when the serum level of vitamin B12 ranged from 125 pmol/L to 250 pmol/L10.

Data analysis was performed with the Statistical Package for the Social Sciences (SPSS) version 16.0. Association of serum vitamin B12 levels with the factors studied was evaluated by Spearman's correlation test, Student's t test or the Mann-Whitney test. All factors associated with the serum vitamin B12 levels with p < 0.2 were included in a linear regression model to determine the factors independently associated, as suggested by Altman11. The variables without normal distribution were transformed into their natural logarithms. Values of p < 0.05 were considered statistically significant.

 

Results

In the period from July 3 to August 13, 2009, 158 eligible patients were identified and all agreed to participate. Two patients were excluded for reporting irregular use of metformin. Twelve patients were excluded for not undergoing blood collection. The analysis was done based on data obtained from 144 patients. Characteristics of these patients are shown in Table 1.

 

 

Serum vitamin B12 levels were low (< 125 pmol/l) in 10 patients (6.9%) and possibly low (125 pmol/L to 250 pmol/L) in 53 patients (36.8%) and were associated with age, estimated vitamin B12 intake and body weight, as shown in Figure 1. The association of metformin dose and duration of metformin use with serum vitamin B12 levels was, respectively, r = -0.114, p = 0.173 and r = -0.128, p = 0.129. Sixty eight patients (47%) had adequate daily intake of vitamin B12 (> 2.4 µg).

 

 

There was no association of serum B12 levels with gender [men (n = 54): 311.6 ± 146.3 pmol/L and women (n = 90): 310.6 ± 161.6 pmol/L, p = 0.97], use of omeprazole [yes (n = 58): 301.0 ± 148.4 pmol/L and no (n=86): 317.8 ± 160.6 pmol/L, p = 0.52], use of calcium [yes (n = 17): 298.7 ± 204.4 pmol/L and no (n = 127): 312.6 ± 148.8 pmol/L, p = 0.79] and red cell MCV (r = 0.035, p = 0.68) and glycosylated hemoglobin (r = 0.092, p = 0.28).

The adjusted model included age, estimated daily intake of vitamin B12, body weight, dose of metformin and duration of metformin use, excluding in two stages the less significant factors. Serum vitamin B12 levels were independently and negatively associated with age (B = -3.17; β = -0.171; p = 0.037) and duration of metformin use (B = -33.36; β= -0.161; p = 0.048), and positively associated with the estimated intake of vitamin B12 (B = 67.96; β = 0.249; p = 0.002), as shown in Table 2.

 

Discussion

In the present study serum vitamin B12 levels were low and possibly low in, respectively, 6.9% and 36.8% of the 144 diabetic patients treated with metformin for more than one year. The prevalence of vitamin B12 deficiency varies according to the cutoff for serum vitamin B12 level used10,12. Ideally, the serum methylmalonic acid would be measured in patients with possibly low serum vitamin B12 levels1,13.

Our results are quite similar to other recent cross sectional studies, that included 195 metformin-treated DM2 patients4: 79 (40.5%) had serum vitamin B12 levels between 73.8 and 258.3 pmol/L. Forty-three of these patients had elevation of either methylmalonic acid or homocysteine levels.

Although most studies associate vitamin B12 deficiency to prolonged use of metformin, a randomized study involving 400 patients with DM2 showed that within only 16 weeks of metformin use, patients had their mean serum folate and vitamin B12 levels reduced in 7% and 14%, respectively, and a 4% increase in mean serum homocysteine levels14.

Since the only source of this vitamin is food, diet has great importance in the prevention of its deficiency, nevertheless, the lack of a strong correlation between estimated daily intake of vit-amin B12 and serum vitamin B12 levels is possibly due to this micronutrient store in the liver13. The method used in our study to estimate vitamin B12 intake is also subject to error; furthermore some day to day variability in food intake is expected. Although estimating vitamin B12 content in food is not precise, it allowed us to assess an additional factor that could influence serum levels of this vitamin. Even though the South of Brazil is a region where red meat is an everyday food, most of the population evaluated had an estimated vitamin B12 intake below the minimum RDI. Nutritional deficiency could have contributed to the low serum vitamin B12 levels in our patients.

Serum vitamin B12 levels were inversely associated with age. Studies evaluating the elderly population of industrialized countries have shown prevalence of vitamin B12 deficiency of around 20%13, implicating age as a possible risk factor for vitamin B12 deficiency.

In this study, serum vitamin B12 levels were not associated with the dose of metformin, but were associated with treatment duration. In a case-control study that included 155 diabetic patients with vitamin B12 deficiency, both emerged as independent risk factors for vitamin B12 deficiency, after adjusting for potential confounding factors3. This discordance could be at least in part explained by the self-report method used in this study to determine the dose and duration of metformin use. Metformin has adverse effects such as diarrhea, nausea and change in taste15, which could cause underreported irregular use.

This study has important limitations. Its design only makes it possible to evaluate associations. The absence of a control group makes it impossible to compare prevalence of vitamin B12 deficiency in a similar population not using metformin, which may have vitamin B12 deficiency associated with other factors, such as described in the Framingham study16. Nevertheless, a recent randomized controlled clinical trial demonstrated an increased risk of vitamin B-12 deficiency in long term treatment with metformin17.

Although serum vitamin B12 level is the most used test to diagnose deficiency of this vitamin18,19 due to its low cost19, its sensitivity is not very high. It can be in the normal range in a significant proportion of patients with disabilities in which serum homocysteine or methylmalonic acid levels allow the early identification of vitamin B12 deficiency18. The large number of metformin-treated DM2 patients at risk for vitamin B12 deficiency makes it important to have better tests to clearly diagnose this condition, prior to committing these patients to lifelong treatment with vitamin B12. Although our study did not answer several questions, we believe it is important to call the medical community's attention to this common problem.

 

References

1. Dali-Youcef N, Andres E. An update on cobalamin deficiency in adults. QJM. 2009; 102(1):17-28.         [ Links ]

2. American Diabetes Association. Standards of medical care in diabetes--2010. Diabetes Care. 2010; 33(Suppl 1):S11-61.         [ Links ]

3. Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM. Risk factors of vitamin B(12) deficiency in patients receiving metformin. Arch Intern Med. 2006; 166(18):1975-9.         [ Links ]

4. Pflipsen MC, Oh RC, Saguil A, Seehusen DA, Topolski R. The prevalence of vitamin B(12) deficiency in patients with type 2 diabetes: a cross-sectional study. J Am Board Fam Med. 2009; 22(5):528-34.         [ Links ]

5. Wile DJ, Toth C. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care. 2010; 33(1):156-61.         [ Links ]

6. Lopes RPSL, Botelho RBA. Álbum fotográfico de porções alimentares. São Paulo: Metha; 2008.         [ Links ]

7. Pinheiro ABV, Lacerda EMA, Benzecry EH, Gomes MCS, Costa VM. Tabela para avaliação de consumo alimentar em medidas caseiras. 5ª ed. São Paulo: Atheneu; 2004.         [ Links ]

8. Philippi ST. Tabela de composição de alimentos: suporte para decisão nutricional. 2ª ed. São Paulo: Coronário; 2002.         [ Links ]

9. Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin b6, folate, vitamin B12, pantothenic acid, biotin, and coline. Washington (DC): National Academy Press; 1998.         [ Links ]

10. Hvas AM, Nexo E. Diagnosis and treatment of vitamin B12 deficiency--an update. Haematologica. 2006; 91(11):1506-12.         [ Links ]

11. Altman DG. Relation between several variables. In: Practical statistics for medical research. London: Chapman & Hall/CRC; 1991.         [ Links ]

12. Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr. 1999; 19(3):357-77.         [ Links ]

13. Andres E, Vidal-Alaball J, Federici L, Loukili NH, Zimmer J, Kaltenbach G. Clinical aspects of cobalamin deficiency in elderly patients. Epidemiology, causes, clinical manifestations, and treatment with special focus on oral cobalamin therapy. Eur J Int Med. 2007; 18(6):456-62.         [ Links ]

14. Wulffele MG, Kooy A, Lehert P, Bets D, Ogterop JC, Borger van der Burg B, et al. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med. 2003; 254(5):455-63.         [ Links ]

15. Schwartz S, Fonseca V, Berner B, Cramer M, Chiang YK, Lewin A. Efficacy, tolerability, and safety of a novel once-daily extended-release metformin in patients with type 2 diabetes. Diabetes Care. 2006; 29(4):759-64.         [ Links ]

16. Lindenbaum J, Rosenberg IH, Wilson PW, Stabler SP, Allen RH. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr. 1994; 60(1):2-11.         [ Links ]

17. Jager J, Kooy A, Lehert P, Wulffele MG, Van der Kolk J, Bets D, 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:c2181.         [ Links ]

18. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol. 1990; 34(2):99-107.         [ Links ]

19. Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology Am Soc Hematol Educ Program. 2003:62-81.         [ Links ]

 

 

Correspondence to:
Tania Weber Furlanetto
Rua Ramiro Barcellos, 2350/700, Bairro Santa Cecília
Porto Alegre - RS, CEP: 90035-903
Tel/ Fax: 51 3359-8152
furlanet@cpovo.net

Submitted on: 10/11/2010
Approved on: 10/27/2010
Financial Support: Fundo de incentivo à Pesquisa e Eventos do Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil
Conflict of interest: None.

 

 

Study conducted at Serviço de Medicina Interna, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS

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