Klin Padiatr 2022; 234(04): 221-227
DOI: 10.1055/a-1702-2614
Original Article

Does Metformin Treatment in Pediatric Population Cause Vitamin B12 Deficiency?

Verursacht die Metformin–Behandlung bei Kindern und Jugendlichen einen Vitamin-B12–Mangel?
Özen Taş
1   Ankara University Faculty of Medicine, Ankara University, Ankara, Turkey
,
Tugba Kontbay
2   Ankara University Faculty of Medicine, Pediatric Endocrinology, Ankara, Turkey
,
Ozlem Dogan
3   Ankara University Faculty of Medicine, Biochemistry, Ankara, Turkey
,
Engin Kose
4   Ankara University Faculty of Medicine, Pediatric Metabolism, Ankara, Turkey
,
Merih Berberoglu
2   Ankara University Faculty of Medicine, Pediatric Endocrinology, Ankara, Turkey
,
Zeynep Siklar
2   Ankara University Faculty of Medicine, Pediatric Endocrinology, Ankara, Turkey
,
Leyla Tumer
5   Gazi University Faculty of Medicine, Department of Pediatric Metabolic Diseases, Ankara, Turkey
,
Fatma Tuba Eminoglu
4   Ankara University Faculty of Medicine, Pediatric Metabolism, Ankara, Turkey
› Author Affiliations

Abstract

Background/Aim There have been no studies to date examining the effect of metformin treatment on vitamin B12 status in children and adolescents. In this prospective study, the effects of metformin on blood vitamin B12, serum methylmalonic acid (MMA), homocysteine and holo-transcobalamin-II (holo-TC-II) levels were assessed in pediatric age group.

Materials and Methods This prospective study was conducted at the Pediatric Endocrinology and Adolescent Department between January 2017 and March 2019. Metabolic syndrome and polycystic ovary syndrome diagnosed patients with insulin resistance and/or impaired glucose tolerance, patients with type 2 diabetes mellitus (DM) treated with metformin were enrolled in study. Blood vitamin B12, MMA, homocysteine, holo-TC-II levels and hemogram values were evaluated.

Results Twenty-four patients were enrolled in study. Among these, 15 (62.5%) were female. The mean age of patients was 13.7±2.3 (10–19) years. Sixteen patients were diagnosed with metabolic syndrome and 8 patients were type 2 DM. At 6-month follow-up of all patients, there was no statistically significant difference in terms of vitamin B12, homocysteine, MMA and holo-TC-II levels. A 0.6% decline in vitamin B12 levels were revealed. At 12-month follow-up of 11 patients (45.8%) (6 Type 2 DM, 5 metabolic syndrome), no statistically significant difference was determined in vitamin B12, homocysteine, MMA and holo-TC-II levels. There were 6% decline in vitamin B12 levels and 10.9% increase in homocysteine levels, 5.4% decrease was detected in holo-TC-II level.

Conclusion Although no significant changes in the serum vitamin B12, homocysteine, MMA or holo-TC-II levels with metformin therapy were detected, long-term prospective studies with high-dose metformin treatment in pediatric population are needed to confirm our results.

Zusammenfassung

Hintergrund Bislang gibt es keine Studien, die die Auswirkungen einer Metformin-Behandlung auf den Vitamin-B12-Status bei Kindern und Jugendlichen untersuchen. In dieser prospektiven Studie wurden die Auswirkungen von Metformin auf den Vitamin-B12-Spiegel im Blut, die Methylmalonsäure (MMA) im Serum, Homocystein und Holo-Transcobalamin-II (Holo-TC-II) in der pädiatrischen Altersgruppe untersucht.

Materialien und Methoden Diese prospektive Studie wurde zwischen Januar 2017 und März 2019 in der Abteilung für pädiatrische Endokrinologie und Jugendmedizin durchgeführt. An der Studie nahmen Patienten mit Metabolischem Syndrom und polyzystischem Ovarsyndrom teil, bei denen eine Insulinresistenz und/oder eine gestörte Glukosetoleranz diagnostiziert wurde, sowie Patienten mit Diabetes mellitus Typ 2 (DM), die mit Metformin behandelt wurden. Die Blutwerte von Vitamin B12, MMA, Homocystein, Holo-TC-II und das Blutbild wurden ausgewertet.

Ergebnisse Vierundzwanzig Patienten wurden in die Studie aufgenommen. Von ihnen waren 15 (62,5%) weiblich. Das Durchschnittsalter der Patienten betrug 13,7±2,3 (10–19) Jahre. Bei sechzehn Patienten wurde ein metabolisches Syndrom und bei 8 Patienten Typ-2-DM diagnostiziert. Bei der 6-monatigen Nachuntersuchung aller Patienten gab es keine statistisch signifikanten Unterschiede in Bezug auf die Vitamin-B12-, Homocystein-, MMA- und Holo-TC-II-Werte. Bei den Vitamin-B12-Werten wurde ein Rückgang um 0,6% festgestellt. Bei der 12-monatigen Nachbeobachtung von 11 Patienten (45,8%) (6 Typ-2-DM, 5 metabolisches Syndrom) wurde kein statistisch signifikanter Unterschied bei den Vitamin-B12-, Homocystein-, MMA- und Holo-TC-II-Werten festgestellt. Der Vitamin-B12-Spiegel sank um 6%, der Homocysteinspiegel stieg um 10,9% und der Holo-TC-II-Spiegel ging um 5,4% zurück.

Schlussfolgerung Obwohl keine signifikanten Veränderungen der Serum-Vitamin-B12-, Homocystein-, MMA- oder Holo-TC-II-Spiegel unter Metformin-Behandlung festgestellt wurden, sind langfristige prospektive Studien mit hochdosierter Metformin-Behandlung in der pädiatrischen Altersgruppe erforderlich, um unsere Ergebnisse zu bestätigen.



Publication History

Received: 09 August 2021
Received: 16 November 2021

Accepted: 18 November 2021

Article published online:
03 February 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 American Diabetes Association. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2020. Diabetes Care 2020; 43: S14-S31
  • 2 American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2019. Diabetes Care 2019; 42: S90-S102.3
  • 3 Aparicio-Ugarriza R, Palacios G. et al. A review of the cut-off points for the diagnosis of vitamin B12 deficiency in the general population. Clin Chem Lab Med 2015; 53: 1149-1159
  • 4 Aroda VR, Edelstein SL, Goldberg RB. et al. Diabetes Prevention Program Research Group. Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab 2016; 101: 1754-1761
  • 5 Berchtold P, Bolli P, Arbenz U. et al. Disturbance of intestinal absorption following metformin therapy. Diabetologia 1969; 5: 405-412
  • 6 Beulens J, Hart H, Kujis R. et al. Influence of duration and dose of metformin on cobalamin deficiency in type 2 diabetes patients using metformin. Acta Diabetologica 2015; 52: 47-53
  • 7 Brug J, van Stralen MM, Te Velde SJ. et al. Differences in weight status and energy-balance related behaviors among schoolchildren across Europe: the ENERGY-project. PLoS One 2012; 7: e34742
  • 8 de Benoist B. Conclusions of a WHO Technical Consultation on folate and vitamin B12 deficiencies. Food Nutr Bull 2008; 29: S238-S244
  • 9 Chen S, Lansdown AJ, Moat SJ. et al. An observational study of the effect of metformin on B12 status and peripheral neuropathy. The British Journal of Diabetes & Vascular Disease 2012; 12: 189-193
  • 10 Garrido-Miguel M, Cavero-Redondo I, Álvarez-Bueno C. et al. Prevalence and Trends of Overweight and Obesity in European Children From 1999 to 2016: A Systematic Review and Meta-analysis. JAMA Pediatr 2019; 173: e192430
  • 11 Gourgari E, Nella AA, Lodish M. et al. Vitamin B12 deficiency in an adolescent girl with polycystic ovarian syndrome. Eur J Obstet Gynecol Reprod Biol 2014; 179: 254
  • 12 Greibe E, Trolle B, Bor MV. et al. Metformin lowers serum cobalamin without changing other markers of cobalamin status: a study on women with polycystic ovary syndrome. Nutrients 2013; 5: 2475-2482
  • 13 Grossman DC, Bibbins-Domingo K, Curry SJ. et al. Screening for Obesity in Children and Adolescents: US Preventive Services Task Force Recommendation Statement. JAMA 2017; 317: 2417-2426
  • 14 Hoogeveen EK, Kostense PJ, Jakobs C. et al. Does metformin increase the serum total homocysteine level in non-insulin-dependent diabetes mellitus?. J Intern Med 1997; 242: 389-394
  • 15 Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ 2014; 349: g5226-g5226
  • 16 Iftikhar R, Kamran SM, Qadir A. et al. Prevalence of vitamin B12 deficiency in patients of type 2 diabetes mellitus on metformin: a case control study from Pakistan. Pan Afr Med J 2013; 16: 67
  • 17 Jiwoon K, Chul Woo A, Sungsoon F. et al. Association between metformin dose and vitamin B12 deficiency in patients in type 2 diabetes. Medicine 2019; 98: 179-181
  • 18 Kanti G, Anadol-Schmitz E, Bobrov P. et al. GDS Group. Vitamin B12 and Folate Concentrations in Recent-onset Type 2 Diabetes and the Effect of Metformin Treatment. J Clin Endocrinol Metab 2020; 105: dgaa150
  • 19 Karabouta Z, Barnett S, Shield JP. et al. Peripheral neuropathy is an early complication of type 2 diabetes in adolescence. Pediatr Diabetes 2008; 9: 110-114
  • 20 Lakso H, Appelblad P, Schneede J. Quantification of Methylmalonic Acid in Human Plasma with Hydrophilic Interaction Liquid Chromatography Separation and MS Detection. Clinical Chemistry 2008; 54: 2028-2035
  • 21 Lindenbaum J, Savage DG, Stabler SP. et al. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol 1990; 34: 99-107
  • 22 Pongchaidecha M, Srikusalanukul V, Chattananon A. et al. Effect of metformin on plasma homocysteine, vitamin B12 and folic acid: a cross-sectional study in patients with type 2 diabetes mellitus. J Med Assoc Thai 2004; 87: 780-787
  • 23 Refsum H, Smith AD, Ueland PM. et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004; 50: 3-32
  • 24 Reinstatler L, Qi YP, Williamson RS. et al. Jr. Association of biochemical B (12) deficiency with metformin therapy and vitamin B (12) supplements: the National Health and Nutrition Examination Survey, 1999-2006. Diabetes Care 2012; 35: 327-333
  • 25 Sato Y, Ouchi K, Funase Y. et al. Relationship between metformin use, vitamin B12 deficiency, hyperhomocysteinemia and vascular complications in patients with type 2 diabetes. Endocr J 2013; 60: 1275-1280
  • 26 Standards of Medical Care in Diabetes-2017: Summary of Revisions. Diabetes Care 2017; 40: S4-S5
  • 27 Ubbink JB, van der Merwe A, Delport R. et al. The effect of a subnormal vitamin B-6 status on homocysteine metabolism. J Clin Invest 1996; 98: 177-184
  • 28 Valente E, Scott JM, Ueland PM. et al. Diagnostic Accuracy of Holotranscobalamin, Methylmalonic Acid, Serum Cobalamin, and Other Indicators of Tissue Vitamin B12 Status in the Elderly. Clinical Chemistry 2011; 57: 856-863
  • 29 Van Guldener C, Stam F, Stehouwer CD. Homocysteine metabolism in renal failure. Kidney Int Suppl 2001; 78: 234-237
  • 30 Vashi P, Edwin P, Popiel B. et al. Methylmalonic Acid and Homocysteine as Indicators of Vitamin B-12 Deficiency in Cancer. PLoS One 2016; 11: e0147843
  • 31 Wijnhoven TM, van Raaij JM, Spinelli A. et al. WHO European Childhood Obesity Surveillance Initiative 2008: weight, height and body mass index in 6-9-year-old children. Pediatr Obes 2013; 8: 79-97
  • 32 Wile DJ, Toth C. Association of metformin, elevated homocysteine and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care 2010; 33: 156-161
  • 33 Wulffele MG, Kooy A, Lehert P. 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: 455-463
  • 34 Zimmet P, Alberti KG, Kaufman F. et al. IDF Consensus Group. The metabolic syndrome in children and adolescents - an IDF consensus report. Pediatr Diabetes 2007; 8: 299-306