DEFICIENCIA DE VITAMINA B12 RELACIONADA AL USO DE METFORMINA ARTÍCULO DE REVISIÓN

Edwin Arauz Valdes; Denise Cardoze; Abdullah Salehji Bhana; Aillyn Liguas

Enviado octubre 28, 2024

Publicado 2026-02-02

Artículos de Investigación

Vol. 33 Núm. 1 (2020): Revista Médico Científica

DEFICIENCIA DE VITAMINA B12 RELACIONADA AL USO DE METFORMINA ARTÍCULO DE REVISIÓN

Edwin Arauz Valdes⁺⁻
Denise Cardoze⁺⁻
Abdullah Salehji Bhana⁺⁻
Aillyn Liguas⁺⁻

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DOI: ND

Publicado: 2026-02-02

Derechos de autor 2024 Revista médico científica

Esta obra está bajo una licencia internacional Creative Commons Atribución-NoComercial-CompartirIgual 4.0.

Resumen

ANTECEDENTES: La diabetes mellitus es una enfermedad metabólica de etiología diversa y alta prevalencia a nivel mundial, en el 2019 se estimó 463 millones de casos y su tendencia va en aumento. La metformina es el medicamento más utilizado en pacientes con diabetes mellitus tipo 2. La deficiencia de vitamina B12 es un efecto adverso de este, pero muy poco estudiado. Factores como: edad, sexo, dosis, duración del tratamiento, entre otros; han sido relacionados al desarrollo de esta complicación.

OBJETIVO: Recopilar y sintetizar información actualizada acerca de la deficiencia de vitamina B12 secundaria al uso de metformina, su mecanismo y los factores de riesgo relacionados.

DISEÑO: Se recolectaron artículos de revisión, trabajos de investigación y metaanálisis de bases de datos científicas como PubMed, Scielo, Cochrane y Science Direct. Los artículos seleccionados fueron publicados entre 2010 a 2020.

CONCLUSIÓN: Las recomendaciones sobre estudios de tamizaje para detectar la deficiencia de vitamina B12 a usuarios de metformina aún no son claras y no se encuentran en guías. Factores como el uso prolongado y la dosis del tratamiento están relacionados a su desarrollo. Esta población se beneficia de la monitorización y de la suplementación dependiendo del riesgo.

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Kanter J, Bornfeldt K. Impact of Diabetes Mellitus | Arteriosclerosis, Thrombosis, and Vascular Biology [Internet]. 2016 [Consultado 4 Jun 2020] 36:1049-1053. Disponible en: https://www.ahajournals.org/doi/10.1161/ATVBAHA.116.30730
Guthrie RA, Guthrie DW. Pathophysiology of diabetes mellitus. Crit Care Nurs Q [Internet]. 2004 [Consultado 28 May 2020];27(2):113?125. Disponible en: https://pubmed.ncbi.nlm.nih.gov/15137354/
International Diabetes Federation. IDF Diabetes Atlas, 9th edn. Brussels, Belgium [Internet]: 2019 [Consultado 28 May 2020]. Disponible en: https://www.diabetesatlas.org
American Diabetes Association. Standards Of Medical Care in Diabetes. The Journal of CliniCal and applied research and education [Internet]. 2020 [Consultado 28 May 2020]. Disponible en: https://care.diabetesjournals.org/content/diacare/suppl/2019/12/20/43.Supplement_1.DC1/Standards_of_Care_2020.pdf
Sanchez-Rangel E, Inzucchi SE. Metformin: clinical use in type 2 diabetes. Diabetologia [Internet]. 2017 [Consultado 30 May 2020];60(9):1586?1593. Disponible en: https://pubmed.ncbi.nlm.nih.gov/28770321/
Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) [Internet]. 2012 [Consultado 30 May 2020];122(6):253?270. doi:10.1042/CS20110386. Disponible en: https://pubmed.ncbi.nlm.nih.gov/22117616/
Shipton MJ, Thachil J. Vitamin B12 deficiency - A 21st century perspective. Clin Med (Lond) [Internet]. 2015 [Consultado 30 May 2020];15(2):145?150. Disponible en: https://pubmed.ncbi.nlm.nih.gov/25824066/
Aroda VR, Edelstein SL, Goldberg RB, et al. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab [Internet]. 2016 [Consultado 30 May 2020];101(4):1754?1761. Disponible en: https://pubmed.ncbi.nlm.nih.gov/26900641/
Tomkin GH, Hadden DR, Weaver JA, Montgomery DA. Vitamin-B12 status of patients on long-term metformin therapy. Br Med J [Internet]. 1971 [Consultado 30 May 2020];2(5763):685?687. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1796258/
Ahmed MA. Metformin and Vitamin B12 Deficiency: Where Do We Stand? J Pharm Pharm Sci [Internet]. 2016 [Consultado 30 May 2020];19(3):382?398. Disponible en: https://pubmed.ncbi.nlm.nih.gov/27806244/
A. Victor Hoffbrand. Anemias Megaloblásticas. Jameson J, Fauci A, Kasper D. Harrison Principios de Medicina Interna Capítulo 95. 20th ed. Ciudad de México: McGraw-Hill; 2018. p699
Allen LH, Miller JW, de Groot L, et al. Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review. J Nutr [Internet]. 2018 [Consultado 30 May 2020];148(suppl_4):1995S?2027S. doi:10.1093/jn/nxy201. Disponible en: https://pubmed.ncbi.nlm.nih.gov/30500928/
Forrellat Barrios Mariela, Gómis Hernández Irma, Gautier du Défaix Gómez Hortensia. Vitamina B12: metabolismo y aspectos clínicos de su deficiencia. Rev Cubana Hematol Inmunol Hemoter [Internet]. 1999 Dic [citado 2020 Jun 03];15(3):159?174. Disponible en: http://scielo.sld.cu/scielo.php?script=sci_arttext&pid=S0864-02891999000300001&lng=es
Clinical Manifestations and Diagnosis of Vitamin B12 and Folate Deficiency. Means R, Fairfield K. UpToDate [Internet]. Uptodate.com. 2020 [citado 2020 Jun 03]. Disponible en: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?csi=0e3d01bd-d8ec-4735-914a-85aebd0d494b&source=contentShare
Markowicz-Piasecka M, Huttunen KM, Mateusiak L, Mikiciuk-Olasik E, Sikora J. Is Metformin a Perfect Drug? Updates in Pharmacokinetics and Pharmacodynamics. Curr Pharm Des [Internet]. 2017 [Citado 29 may 2020];23(17):2532?2550. Disponible en: http://www.eurekaselect.com/147864/article
McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia [Internet]. 2016 [Citado 29 may 2020];59(3):426?435. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742508/
Thomas I, Gregg B. Metformin; a review of its history and future: from lilac to longevity. Pediatr Diabetes [Internet]. 2017 [Citado 29 may 2020];18(1):10?16. Disponible en: https://deepblue.lib.umich.edu/bitstream/handle/2027.42/135516/pedi12473.pdf?sequence=2&isAllowed=y
Flory J, Lipska K. Metformin in 2019. JAMA [Internet]. 2019 [Citado 29 may 2020];321(19):1926?1927. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790897/
Shivaprasad C, Gautham K, Ramdas B, Gopaldatta KS, Nishchitha K. Metformin Usage Index and assessment of vitamin B12 deficiency among metformin and non-metformin users with type 2 diabetes mellitus [published online ahead of print, 2020 Apr 7]. Acta Diabetol [Internet]. 2020;10.1007/s00592-020-01526-4. doi:10.1007/s00592-020-01526-4. Disponible en: https://pubmed.ncbi.nlm.nih.gov/32266492/
Langan RC, Goodbred AJ. Vitamin B12 Deficiency: Recognition and Management. Am Fam Physician [Internet]. 2017 [Citado 29 may 2020];96(6):384?389. Disponible en: https://pubmed.ncbi.nlm.nih.gov/28925645/?dopt=Abstract
Sukumar N, Saravanan P. Investigating vitamin B12 deficiency. BMJ [Internet]. 2019 [Consultado 28 May 2020];:l1865. Disponible en: https://www.bmj.com/content/365/bmj.l1865
Ko SH, Ko SH, Ahn YB, et al. Association of vitamin B12 deficiency and metformin use in patients with type 2 diabetes. J Korean Med Sci [Internet]. 2014 [Consultado 30 May 2020];29(7):965?972. Disponible en: https://pubmed.ncbi.nlm.nih.gov/25045229/
Kang D, Yun JS, Ko SH, et al. Higher prevalence of metformin-induced vitamin B12 deficiency in sulfonylurea combination compared with insulin combination in patients with type 2 diabetes: a cross-sectional study. PLoS One [Internet]. 2014 [Consultado 28 May 2020];9(10)
. Published 2014 Oct 9. Disponible en: https://pubmed.ncbi.nlm.nih.gov/25299054/
Owhin SO, Adaja TM, Fasipe OJ, Akhideno PE, Kalejaiye OO et al. Prevalence of vitamin B12 deficiency among metformin-treated type 2 diabetic patients in a tertiary institution, South-South Nigeria. SAGE Open Med [Internet]. 2019 [Consultado 28 May 2020];7:2050312119853433. Published 2019 May 23. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535731/
Alvarez M, Sierra OR, Saavedra G, Moreno S. Vitamin B12 deficiency and diabetic neuropathy in patients taking metformin: a cross-sectional study. Endocr Connect [Internet]. 2019 [Citado 29 may 2020];8(10):1324?1329. Disponible en:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790897/
Ahmed MA, Muntingh G, Rheeder P. Vitamin B12 deficiency in metformin-treated type-2 diabetes patients, prevalence and association with peripheral neuropathy. BMC Pharmacol Toxicol [Internet]. 2016 [Citado 29 may 2020];17(1):44. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054613/
Kancherla V, Elliott JL Jr, Patel BB, et al. Long-term Metformin Therapy and Monitoring for Vitamin B12 Deficiency Among Older Veterans. J Am Geriatr Soc [Internet]. 2017 [Citado 29 may 2020];65(5):1061?1066. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435502/
Kim J, Ahn CW, Fang S, Lee HS, Park JS. Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes. Medicine (Baltimore) [Internet]. 2019 [Citado 29 may 2020];98(46)
. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867725/
Iftikhar R, Kamran SM, Qadir A, Iqbal Z, bin Usman H. Prevalence of vitamin B12 deficiency in patients of type 2 diabetes mellitus on metformin: a case control study from Pakistan. Pan Afr Med J [Internet]. 2013 [Citado 29 may 2020];16:67.
Khan A, Shafiq I, Hassan Shah M. Prevalence of Vitamin B12 Deficiency in Patients with Type II Diabetes Mellitus on Metformin: A Study from Khyber Pakhtunkhwa. Cureus [Internet]. 2017 [Citado 29 may 2020];9(8)
. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647126/
Nervo M, Lubini A, Raimundo FV, et al. Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil. Rev Assoc Med Bras (1992) [Internet]. 2011 [Consultado 29 May 2020];57(1):46?49. Disponible en: https://pubmed.ncbi.nlm.nih.gov/21390459/
Damião CP, Rodrigues AO, Pinheiro MF, et al. Prevalence of vitamin B12 deficiency in type 2 diabetic patients using metformin: a cross-sectional study. Sao Paulo Med J [Internet]. 2016 [Consultado 29 May 2020];134(6):473?479. Disponible en: https://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802016005004103&lng=en&nrm=iso&tlng=en
Biemans E, Hart HE, Rutten GE, Cuellar Renteria VG, Kooijman-Buiting AM, Beulens JW. Cobalamin status and its relation with depression, cognition and neuropathy in patients with type 2 diabetes mellitus using metformin. Acta Diabetol [Internet]. 2015 [Consultado 29 May 2020];52(2):383?393. Disponible en: https://pubmed.ncbi.nlm.nih.gov/25315630/
Niafar M, Hai F, Porhomayon J, Nader ND. The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med [Internet]. 2015 [Consultado 2 Jun 2020];10(1):93?102. Disponible en: https://pubmed.ncbi.nlm.nih.gov/25502588/
Chapman LE, Darling AL, Brown JE. Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab [Internet]. 2016 [Consultado 2 Jun 2020];42(5):316?327. Disponible en: https://pubmed.ncbi.nlm.nih.gov/27130885/
Beulens JW, Hart HE, Kuijs R, Kooijman-Buiting AM, Rutten GE. Influence of duration and dose of metformin on cobalamin deficiency in type 2 diabetes patients using metformin. Acta Diabetol [Internet]. 2015 [Consultado 3 Jun 2020];52(1):47?53. Disponible en: https://pubmed.ncbi.nlm.nih.gov/24908579/
Wile DJ, Toth C. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care [Internet]. 2010 [Consultado 3 Jun 2020];33(1):156?161. Disponible en: https://pubmed.ncbi.nlm.nih.gov/19846797/
Liu Q, Li S, Quan H, Li J. Vitamin B12 status in metformin treated patients: systematic review. PLoS One [Internet]. 2014 [Consultado 2 Jun 2020];9(6)
. Published 2014 Jun 24. Disponible en: https://pubmed.ncbi.nlm.nih.gov/24959880/
Yang W, Cai X, Wu H, Ji L. Associations between metformin use and vitamin B12 levels, anemia, and neuropathy in patients with diabetes: a meta-analysis. J Diabetes [Internet]. 2019 [Consultado 3 Jun 2020];11(9):729?743. Disponible en: https://pubmed.ncbi.nlm.nih.gov/30615306/

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[1] Kanter J, Bornfeldt K. Impact of Diabetes Mellitus | Arteriosclerosis, Thrombosis, and Vascular Biology [Internet]. 2016 [Consultado 4 Jun 2020] 36:1049-1053. Disponible en: https://www.ahajournals.org/doi/10.1161/ATVBAHA.116.30730

[2] Guthrie RA, Guthrie DW. Pathophysiology of diabetes mellitus. Crit Care Nurs Q [Internet]. 2004 [Consultado 28 May 2020];27(2):113?125. Disponible en: https://pubmed.ncbi.nlm.nih.gov/15137354/

[3] International Diabetes Federation. IDF Diabetes Atlas, 9th edn. Brussels, Belgium [Internet]: 2019 [Consultado 28 May 2020]. Disponible en: https://www.diabetesatlas.org

[4] American Diabetes Association. Standards Of Medical Care in Diabetes. The Journal of CliniCal and applied research and education [Internet]. 2020 [Consultado 28 May 2020]. Disponible en: https://care.diabetesjournals.org/content/diacare/suppl/2019/12/20/43.Supplement_1.DC1/Standards_of_Care_2020.pdf

[5] Sanchez-Rangel E, Inzucchi SE. Metformin: clinical use in type 2 diabetes. Diabetologia [Internet]. 2017 [Consultado 30 May 2020];60(9):1586?1593. Disponible en: https://pubmed.ncbi.nlm.nih.gov/28770321/

[6] Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) [Internet]. 2012 [Consultado 30 May 2020];122(6):253?270. doi:10.1042/CS20110386. Disponible en: https://pubmed.ncbi.nlm.nih.gov/22117616/

[7] Shipton MJ, Thachil J. Vitamin B12 deficiency - A 21st century perspective. Clin Med (Lond) [Internet]. 2015 [Consultado 30 May 2020];15(2):145?150. Disponible en: https://pubmed.ncbi.nlm.nih.gov/25824066/

[8] Aroda VR, Edelstein SL, Goldberg RB, et al. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab [Internet]. 2016 [Consultado 30 May 2020];101(4):1754?1761. Disponible en: https://pubmed.ncbi.nlm.nih.gov/26900641/

[9] Tomkin GH, Hadden DR, Weaver JA, Montgomery DA. Vitamin-B12 status of patients on long-term metformin therapy. Br Med J [Internet]. 1971 [Consultado 30 May 2020];2(5763):685?687. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1796258/

[10] Ahmed MA. Metformin and Vitamin B12 Deficiency: Where Do We Stand? J Pharm Pharm Sci [Internet]. 2016 [Consultado 30 May 2020];19(3):382?398. Disponible en: https://pubmed.ncbi.nlm.nih.gov/27806244/

[11] A. Victor Hoffbrand. Anemias Megaloblásticas. Jameson J, Fauci A, Kasper D. Harrison Principios de Medicina Interna Capítulo 95. 20th ed. Ciudad de México: McGraw-Hill; 2018. p699

[12] Allen LH, Miller JW, de Groot L, et al. Biomarkers of Nutrition for Development (BOND): Vitamin B-12 Review. J Nutr [Internet]. 2018 [Consultado 30 May 2020];148(suppl_4):1995S?2027S. doi:10.1093/jn/nxy201. Disponible en: https://pubmed.ncbi.nlm.nih.gov/30500928/

[13] Forrellat Barrios Mariela, Gómis Hernández Irma, Gautier du Défaix Gómez Hortensia. Vitamina B12: metabolismo y aspectos clínicos de su deficiencia. Rev Cubana Hematol Inmunol Hemoter [Internet]. 1999 Dic [citado 2020 Jun 03];15(3):159?174. Disponible en: http://scielo.sld.cu/scielo.php?script=sci_arttext&pid=S0864-02891999000300001&lng=es

[14] Clinical Manifestations and Diagnosis of Vitamin B12 and Folate Deficiency. Means R, Fairfield K. UpToDate [Internet]. Uptodate.com. 2020 [citado 2020 Jun 03]. Disponible en: https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-vitamin-b12-and-folate-deficiency?csi=0e3d01bd-d8ec-4735-914a-85aebd0d494b&source=contentShare

[15] Markowicz-Piasecka M, Huttunen KM, Mateusiak L, Mikiciuk-Olasik E, Sikora J. Is Metformin a Perfect Drug? Updates in Pharmacokinetics and Pharmacodynamics. Curr Pharm Des [Internet]. 2017 [Citado 29 may 2020];23(17):2532?2550. Disponible en: http://www.eurekaselect.com/147864/article

[16] McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia [Internet]. 2016 [Citado 29 may 2020];59(3):426?435. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742508/

[17] Thomas I, Gregg B. Metformin; a review of its history and future: from lilac to longevity. Pediatr Diabetes [Internet]. 2017 [Citado 29 may 2020];18(1):10?16. Disponible en: https://deepblue.lib.umich.edu/bitstream/handle/2027.42/135516/pedi12473.pdf?sequence=2&isAllowed=y

[18] Flory J, Lipska K. Metformin in 2019. JAMA [Internet]. 2019 [Citado 29 may 2020];321(19):1926?1927. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790897/

[19] Shivaprasad C, Gautham K, Ramdas B, Gopaldatta KS, Nishchitha K. Metformin Usage Index and assessment of vitamin B12 deficiency among metformin and non-metformin users with type 2 diabetes mellitus [published online ahead of print, 2020 Apr 7]. Acta Diabetol [Internet]. 2020;10.1007/s00592-020-01526-4. doi:10.1007/s00592-020-01526-4. Disponible en: https://pubmed.ncbi.nlm.nih.gov/32266492/

[20] Langan RC, Goodbred AJ. Vitamin B12 Deficiency: Recognition and Management. Am Fam Physician [Internet]. 2017 [Citado 29 may 2020];96(6):384?389. Disponible en: https://pubmed.ncbi.nlm.nih.gov/28925645/?dopt=Abstract

[21] Sukumar N, Saravanan P. Investigating vitamin B12 deficiency. BMJ [Internet]. 2019 [Consultado 28 May 2020];:l1865. Disponible en: https://www.bmj.com/content/365/bmj.l1865

[22] Ko SH, Ko SH, Ahn YB, et al. Association of vitamin B12 deficiency and metformin use in patients with type 2 diabetes. J Korean Med Sci [Internet]. 2014 [Consultado 30 May 2020];29(7):965?972. Disponible en: https://pubmed.ncbi.nlm.nih.gov/25045229/

[23] Kang D, Yun JS, Ko SH, et al. Higher prevalence of metformin-induced vitamin B12 deficiency in sulfonylurea combination compared with insulin combination in patients with type 2 diabetes: a cross-sectional study. PLoS One [Internet]. 2014 [Consultado 28 May 2020];9(10)

[24] . Published 2014 Oct 9. Disponible en: https://pubmed.ncbi.nlm.nih.gov/25299054/

[25] Owhin SO, Adaja TM, Fasipe OJ, Akhideno PE, Kalejaiye OO et al. Prevalence of vitamin B12 deficiency among metformin-treated type 2 diabetic patients in a tertiary institution, South-South Nigeria. SAGE Open Med [Internet]. 2019 [Consultado 28 May 2020];7:2050312119853433. Published 2019 May 23. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535731/

[26] Alvarez M, Sierra OR, Saavedra G, Moreno S. Vitamin B12 deficiency and diabetic neuropathy in patients taking metformin: a cross-sectional study. Endocr Connect [Internet]. 2019 [Citado 29 may 2020];8(10):1324?1329. Disponible en:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790897/

[27] Ahmed MA, Muntingh G, Rheeder P. Vitamin B12 deficiency in metformin-treated type-2 diabetes patients, prevalence and association with peripheral neuropathy. BMC Pharmacol Toxicol [Internet]. 2016 [Citado 29 may 2020];17(1):44. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054613/

[28] Kancherla V, Elliott JL Jr, Patel BB, et al. Long-term Metformin Therapy and Monitoring for Vitamin B12 Deficiency Among Older Veterans. J Am Geriatr Soc [Internet]. 2017 [Citado 29 may 2020];65(5):1061?1066. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435502/

[29] Kim J, Ahn CW, Fang S, Lee HS, Park JS. Association between metformin dose and vitamin B12 deficiency in patients with type 2 diabetes. Medicine (Baltimore) [Internet]. 2019 [Citado 29 may 2020];98(46)

[30] . Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867725/

[31] Iftikhar R, Kamran SM, Qadir A, Iqbal Z, bin Usman H. Prevalence of vitamin B12 deficiency in patients of type 2 diabetes mellitus on metformin: a case control study from Pakistan. Pan Afr Med J [Internet]. 2013 [Citado 29 may 2020];16:67.

[32] Khan A, Shafiq I, Hassan Shah M. Prevalence of Vitamin B12 Deficiency in Patients with Type II Diabetes Mellitus on Metformin: A Study from Khyber Pakhtunkhwa. Cureus [Internet]. 2017 [Citado 29 may 2020];9(8)

[33] . Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647126/

[34] Nervo M, Lubini A, Raimundo FV, et al. Vitamin B12 in metformin-treated diabetic patients: a cross-sectional study in Brazil. Rev Assoc Med Bras (1992) [Internet]. 2011 [Consultado 29 May 2020];57(1):46?49. Disponible en: https://pubmed.ncbi.nlm.nih.gov/21390459/

[35] Damião CP, Rodrigues AO, Pinheiro MF, et al. Prevalence of vitamin B12 deficiency in type 2 diabetic patients using metformin: a cross-sectional study. Sao Paulo Med J [Internet]. 2016 [Consultado 29 May 2020];134(6):473?479. Disponible en: https://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802016005004103&lng=en&nrm=iso&tlng=en

[36] Biemans E, Hart HE, Rutten GE, Cuellar Renteria VG, Kooijman-Buiting AM, Beulens JW. Cobalamin status and its relation with depression, cognition and neuropathy in patients with type 2 diabetes mellitus using metformin. Acta Diabetol [Internet]. 2015 [Consultado 29 May 2020];52(2):383?393. Disponible en: https://pubmed.ncbi.nlm.nih.gov/25315630/

[37] Niafar M, Hai F, Porhomayon J, Nader ND. The role of metformin on vitamin B12 deficiency: a meta-analysis review. Intern Emerg Med [Internet]. 2015 [Consultado 2 Jun 2020];10(1):93?102. Disponible en: https://pubmed.ncbi.nlm.nih.gov/25502588/

[38] Chapman LE, Darling AL, Brown JE. Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab [Internet]. 2016 [Consultado 2 Jun 2020];42(5):316?327. Disponible en: https://pubmed.ncbi.nlm.nih.gov/27130885/

[39] Beulens JW, Hart HE, Kuijs R, Kooijman-Buiting AM, Rutten GE. Influence of duration and dose of metformin on cobalamin deficiency in type 2 diabetes patients using metformin. Acta Diabetol [Internet]. 2015 [Consultado 3 Jun 2020];52(1):47?53. Disponible en: https://pubmed.ncbi.nlm.nih.gov/24908579/

[40] Wile DJ, Toth C. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care [Internet]. 2010 [Consultado 3 Jun 2020];33(1):156?161. Disponible en: https://pubmed.ncbi.nlm.nih.gov/19846797/

[41] Liu Q, Li S, Quan H, Li J. Vitamin B12 status in metformin treated patients: systematic review. PLoS One [Internet]. 2014 [Consultado 2 Jun 2020];9(6)

[42] . Published 2014 Jun 24. Disponible en: https://pubmed.ncbi.nlm.nih.gov/24959880/

[43] Yang W, Cai X, Wu H, Ji L. Associations between metformin use and vitamin B12 levels, anemia, and neuropathy in patients with diabetes: a meta-analysis. J Diabetes [Internet]. 2019 [Consultado 3 Jun 2020];11(9):729?743. Disponible en: https://pubmed.ncbi.nlm.nih.gov/30615306/

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