European Journal of Nutrition

, Volume 50, Issue 2, pp 97–106 | Cite as

Is a low blood level of vitamin B12 a cardiovascular and diabetes risk factor? A systematic review of cohort studies

  • Snorri B. Rafnsson
  • Ponnusamy Saravanan
  • Raj S. Bhopal
  • Chittaranjan S. Yajnik
Original Contribution



To assess the prior hypothesis that low blood vitamin B12, partly through hyperhomocysteinemia and partly through direct effects, increases the risk of cardiovascular diseases and diabetes. As background, we also extracted all-cause mortality from the studies that met our criteria.


A systematic review of prospective cohort studies identified through searching six electronic databases, screening of reference lists, and citation search. Included studies reported data on the association between vitamin B12 blood levels, or other appropriate surrogate biological markers e.g. holotranscobalamin or serum/urine methylmalonic acid, and fatal or non-fatal incident diabetes and cardiovascular events.


Seven studies were included. Studies differed regarding the population studied, length of follow-up, study outcomes, and data analysis—a narrative synthesis approach was performed to examine the results. Most studies met few of the quality assessment criteria which were adapted from the Scottish Intercollegiate Guidelines Network (SIGN). Only one high-quality study reported that low B12 increased the risk of incident cerebral ischaemia (RR = 1.76; 95% CI = 1.16–2.68). After controlling for homocysteine, the association persisted although weakened (RR = 1.57; 95% CI = 1.02–2.43), suggesting that the effects of low B12 were only partly mediated by homocysteine. In two studies, higher B12 levels were associated with a greater risk of total mortality (RR = 1.00; 95% CI = 1.00–1.00 and HR = 1.15; 95% CI = 1.08–1.22, respectively) and combined fatal and non-fatal coronary events (RR = 1.00; 95% CI = 1.00–1.00). No association between study outcomes and vitamin B12 levels was found in four other studies.


Surprisingly, there is only very limited evidence that vitamin B12 deficiency predisposes to the risk of mortality and morbidity from either cardiovascular diseases or diabetes in adults. Current data do not support vitamin B12 supplementation to reduce the risk of cardiovascular diseases or diabetes.


Vitamin B12 Cardiovascular diseases Diabetes mellitus type 2 Cohort studies Aetiology 


  1. 1.
    Wierzbicki AS (2007) Homocysteine and cardiovascular disease: a review of the evidence. Diab Vasc Dis Res 4:143–150CrossRefGoogle Scholar
  2. 2.
    Strain JJ, Dowey L, Ward M, Pentieva K, McNulty H et al (2004) B-vitamins, homocysteine metabolism and CVD. P Nutr Soc 63:597–603CrossRefGoogle Scholar
  3. 3.
    Rosenberg IH (2008) Metabolic programming of offspring by vitamin B(12)/folate imbalance during pregnancy. Diabetologia 51:6–7CrossRefGoogle Scholar
  4. 4.
    Green R (2009) Is it time for vitamin B-12 fortification? What are the questions? Am J Clin Nutr 89(suppl):712S–716SCrossRefGoogle Scholar
  5. 5.
    Ford ES, Smith SJ, Stroup DF et al (2002) Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies. Int J Epidemiol 31:59–70CrossRefGoogle Scholar
  6. 6.
    Wald DS, Law MR, Wald NJ (2005) Serum homocysteine and coronary heart disease. In: Marmot M, Elliott P et al (eds) Coronary heart disease epidemiology. From aetiology to public health, 2nd edn. Oxford University Press, Oxford, pp 239–250CrossRefGoogle Scholar
  7. 7.
    Virtanen JK, Voutilainen S, Happonen P et al (2005) Serum homocysteine, folate and risk of stroke: Kuopio ischaemic heart disease risk factor (KIHD) study. Eur J Cardiov Prev R 12:369–375CrossRefGoogle Scholar
  8. 8.
    Stabler SP, Allen RH (2004) Vitamin B12 deficiency as a worldwide problem. Annu Rev Nutr 24:299–326CrossRefGoogle Scholar
  9. 9.
    Allen LH (2009) How common is vitamin B-12 deficiency? Am J Clin Nutr 89(suppl):693S–696SCrossRefGoogle Scholar
  10. 10.
    Yajnik CS, Deshpande SS, Jackson AA et al (2008) Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Diabetologia 51:29–38CrossRefGoogle Scholar
  11. 11.
    Krishnaveni GV, Hill JC, Veena SR et al (2009) Low plasma vitamin B12 in pregnancy is associated with gestational ‘diabesity’ and later diabetes. Diabetologia 52:2358–2359CrossRefGoogle Scholar
  12. 12.
    Yajnik CS, Deshmukh US (2008) Maternal nutrition, intrauterine programming and consequential risks in the offspring. Rev Endocr Metab Disord 9:203–211CrossRefGoogle Scholar
  13. 13.
    Bhopal R (2009) Seven mistakes and potential solutions in epidemiology, including a call for a world council of epidemiology and causality. Emerg Themes Epidemiol 6:6CrossRefGoogle Scholar
  14. 14.
    McNulty H, Pentieva K, Hoey L et al (2008) Homocysteine, B-vitamins and CVD. Proc Nutr Soc 67:232–237CrossRefGoogle Scholar
  15. 15.
    Stroup DF, Berlin JA, Morton SC et al (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. J Amer Med Assoc 283:2008–2012CrossRefGoogle Scholar
  16. 16.
    Dangour AD, Breeze E, Clarke R et al (2008) Plasma homocysteine, but not folate or vitamin B12, predicts mortality in older people in the United Kingdom. J Nutr 138:1121–1128Google Scholar
  17. 17.
    Hung J, Beilby JP, Knuiman MW et al (2003) Folate and vitamin B-12 and risk of fatal cardiovascular disease: cohort study from Busselton, Western Australia. Br Med J 326:131CrossRefGoogle Scholar
  18. 18.
    Looker HC, Fagot-Campagna A, Gunter EW et al (2007) Homocysteine and vitamin B(12) concentrations and mortality rates in type 2 diabetes. Diabetes Metab Rev 23:193–201CrossRefGoogle Scholar
  19. 19.
    Zeitlin A, Frishman WH, Chee JC (1997) The association of vitamin B12 and folate blood levels with mortality and cardiovascular morbidity incidence in the old old: The Bronx Aging Study. Am J Ther 4:275–281CrossRefGoogle Scholar
  20. 20.
    de Bree A, Verschuren WMM, Blom HJ et al (2003) Coronary heart disease mortality, plasma homocysteine, and B-vitamins: a prospective study. Atherosclerosis 166:369–377CrossRefGoogle Scholar
  21. 21.
    Folsom AR, Nieto FJ, McGovern PG et al (1998) Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the atherosclerosis Risk in communities (ARIC) study. Circulation 98:204–210Google Scholar
  22. 22.
    Weikert C, Dierkes J, Hoffman K et al (2007) B vitamin plasma levels and the risk of ischemic stroke and transient ischemic attack in a German cohort. Stroke 38:2908–2912CrossRefGoogle Scholar
  23. 23.
    Fibrinogen Studies Collaboration (2005) Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality. An individual participant meta-analysis. J Amer Med Assoc 294:1799–1809CrossRefGoogle Scholar
  24. 24.
    Welsh P, Lowe GDO, Chalmers J et al (2008) Associations of proinflammatory cytokines with the risk of recurrent stroke. Stroke 39:2226–2230CrossRefGoogle Scholar
  25. 25.
    Smith AD, Refsum H (2009) Vitamin B12 and cognition in the elderly. Am J Clin Nutr 89(suppl):707S–711SCrossRefGoogle Scholar
  26. 26.
    Salles N, Herrmann F, Sakbani K et al (2005) High vitamin B12 level: a strong predictor of mortality in elderly inpatients. J Am Geriatr Soc 53:917–918CrossRefGoogle Scholar
  27. 27.
    Hemmersbach-Miller M, Conde-Martel A, León-Betancor P (2005) Vitamin B12 as a predictor of mortality in elderly inpatients. J Am Geriatr Soc 53:2035–2036CrossRefGoogle Scholar
  28. 28.
    Sinclair KD, Allegrucci C, Singh R et al (2007) DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptual B vitamin and methionine status. P Natl Acad Sci USA 104:19351–19356CrossRefGoogle Scholar
  29. 29.
    Egger M, Schneider M, Smith GD (1998) Mata-analysis spurious precision? Meta-analysis of observational studies. Br Med J 316:140–144Google Scholar
  30. 30.
    Lewis SJ, Ebrahim S, Smith GD (2005) Meta-analysis of MTHFR 677C → T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate? Br Med J 331:1053CrossRefGoogle Scholar
  31. 31.
    Namour F, Oliver JL, Abdelmouttaleb I et al (2001) Transcobalamin codon 259 polymorphism in HT-29 and Caco-2 cells and in Caucasians: relation to transcobalamin and homocysteine concentration in blood. Blood 97:1092–1098CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Snorri B. Rafnsson
    • 1
  • Ponnusamy Saravanan
    • 2
  • Raj S. Bhopal
    • 1
  • Chittaranjan S. Yajnik
    • 3
  1. 1.Public Health Sciences Section, School of Clinical Sciences and Community Health and Centre for Population Health SciencesUniversity of EdinburghEdinburghScotland, UK
  2. 2.Clinical Sciences Research Institute, Warwick Medical SchoolCSB, UHCW NHS TrustCoventryUK
  3. 3.Diabetes UnitKEM Hospital and Research CentrePuneIndia

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