HOMOCYSTEINE LOWERING TRIALISTS’ COLLABORATION


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Background: Dietary supplementation with B vitamins that lower blood homocysteine concentrations is expected to reduce cardiovascular disease risk, but there has been uncertainty about the optimum regimen to use for this purpose. Objective: The objectives were to ascertain the lowest dose of folic acid associated with the maximum reduction in homocysteine concentrations and to determine the additional relevance of vitamins B-12 and B-6. Design: A meta-analysis of 25 randomized controlled trials involving individual data on 2596 subjects assessed the effect on plasma homocysteine concentrations of different doses of folic acid and of the addition of vitamins B-12 and B-6. Results: The proportional reductions in plasma homocysteine con-centrations produced by folic acid were greater at higher homocysteine (P<0.001) and lower folate (P<0.001) pretreatment concentrations; they were also greater in women than in men (P<0.001). After standardization for sex and to pretreatment plasma concentrations of 12 mol homocysteine/L and 12 nmolfolate/L, daily doses of 0.2, 0.4, 0.8, 2.0, and 5.0 mg folic acid were associated with reductions in homocysteine of 13% (95% CI: 10%, 16%), 20% (17%, 22%), 23% (21%, 26%), 23% (20%, 26%), and 25% (22%, 28%), respectively. Vitamin B-12 (x: 0.4 mg/d)produced 7% (95% Cl: 4%, 9%) further reduction in homocysteine concentrations, but vitamin B-6 had no significant effect. Conclusions: Daily doses of ≥ 0.8 mg folic acid are typically required to achieve the maximal reduction in plasma homocysteine concentrations produced by folic acid supplementation. Doses of 0.2 and 0.4 mg are associated with 60% and 90%, respectively, of this maximal effect. Am J Clin Nutr 2005;82:806 -12.

Full Text

Restricted Access

About the authors

- -

References

  1. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002; 288(16): 2015-22.
  2. Wald D.S., Law M., Morris J.K. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. Br. Med. J. 2002; 325(7374): 1202-6.
  3. Clarke R., Smith A.D., Jobst K., Sutton L., Refsum H., Ueland P.M. Plasma homocysteine, folate and vitamin B-12 as risk factors for confirmed Alzheimer’s disease. Arch. Neurol. 1998; 55(11): 1449-55.
  4. Selhub J., Jacques P.F., Wilson P.W., Rush D., Rosenberg I.H. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993; 270(22): 2693-8.
  5. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. Br. Med. J. 1998; 316(7135): 894-8.
  6. Clarke R., Armitage J. Vitamin supplements and cardiovascular risk: review of the randomized trials of homocysteine-lowering vitamin supplements. Semin. Thromb. Haemost. 2000; 26(3): 341-8.
  7. Ubbink J.B., van der Merwe A., Vermaak W.J.H., Delport R. Hyperhomocysteinemia and the response to vitamin supplementation. Clin. Investig. 1993; 71(12): 993-8.
  8. Ubbink J.B., Vermaak W.J.H., van der Merwe A., Becker P.J., Delport R., Potgieter H.C. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J. Nutr. 1994; 124(10): 1927-33.
  9. Dierkes J. Vitamin requirements for the reduction of homocysteine blood levels in healthy young women. Diss. Bonn: University of Bonn; 1995.
  10. Saltzjnan E., Mason J.B., Jacques P.F., Selhub J., Salem D., Schaefer E.J. et al. B-vitamin supplementation lowers homocysteine levels in heart disease. Clin. Res. 1994; 42: 172A (abstr.).
  11. Landgren F., Israelsson B., Lindgren A., Hultberg B., Andersson A., Brattström L. Plasma homocysteine in acute myocardial infarcation: homocysteine-lowering effect of folic acid. J. Intern. Med. 1995; 237(4): 381-8.
  12. Naurath H.J., Joosten E., Reizler R., Stabler S.P., Allen R.H., Lindenbaum J. Effects of vitamin B12 folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Lancet. 1995; 364(8967): 85-9.
  13. Cuskelly G., McNulty W., McPartlin J., Strain J.J., Scott J.M. Plasma homocysteine response to folate intervention in young women. Ir. J. Med. Sci. 1995; 164: 3 (abstr.).
  14. Woodside J.V., Yarnell J.W., McMaster D., Young I.S., Harmon D.L., McCrum E.E. et al. The effect of B-vitamins and antioxidant vitamins on hyperhomocysteinemia: a double-blind randomized factorial design controlled trial. Am. J. Clin. Nutr. 1998; 67(5): 858-66.
  15. Malinow M.R., Nieto F.J., Kruger W.D., Duell P.B., Hess D.L., Gluckman R.A. et al. The effects of folic acid supplementation on plasma total homocysteine are modulated by multivitamin use and methylenetetrahydrofolate reductase genotypes. Arterioscler. Thromb. Vasc. Biol. 1997; 17(6): 1157-62.
  16. den Heijer M., Brouwer I.A., Bos G.M., Blom H.J., van der Put N.M., Spaans A.P. et al. Vitamin supplementation reduces blood homocysteine levels: a controlled trial in patients with venous thrombosis and healthy volunteers. Arterioscler. Thromb. Vasc. Biol. 1998; 18(3): 356-61.
  17. Schorah C.J., Devitt H., Lucock M., Dowell A.C. The responsiveness of plasma homocysteine to small increases in dietary folic acid: a primary care study. Eur. J. Clin. Nutr. 1998; 52(6): 407-11.
  18. Malinow M.R., Duell P.B., Hess D.L., Anderson P.H., Kruger W.D., Phillipson B.E. et al. Reduction of plasma homocyst(e)ine levels by breakfast cereals fortified with folic acid in patients with coronary heart disease. N. Engl. J. Med. 1998; 338(15): 1009-15.
  19. Bronstrup A. Effects of single and combined B-vitamin supplementation on homocysteine concentrations in different population groups. Diss. Bonn: University of Bonn; 1998.
  20. Dierkes J., Kroesen M., Pietrzik K. Folic acid and vitamin B6 supplementation and plasma homocysteine concentrations in healthy young women. Int. J. Vitam. Nutr. Res. 1998; 68(2): 98-103.
  21. Brouwer I.A., van Dusseldorp M., Thomas C.M., Duran M., Hautvast J.G., Eskes T.K. et al. Low-dose folic acid supplementation decreases plasma homocysteine: a randomized trial. Am. J. Clin. Nutr. 1999; 69(1): 99-104.
  22. MacMahon M., Kirkpatrick C., Cummings C.E., Clayton A., Robinson P.J., Tomiak R.H. et al. A pilot study with Simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH). Nutr. Metab. Cardiovasc. Dis. 2000; 10(4): 195-203.
  23. Thambyrajah J., Landray M.J., McGlynn F.J., Jones H.J., Wheeler D.C., Townend J.N. Does folic acid decrease plasma homocysteine and improve endothelial function in patients with predialysis renal failure? Circulation. 2000; 102(8): 871-5.
  24. Wald D.S., Bishop L., Wald N.J., Law M., Hennessy E., Weir D. et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch. Intern. Med. 2001; 161(5): 695-700.
  25. Thambyrajah J., Landray M.J., Jones H.J., McGlynn F.J., Wheeler D.C., Townend J.N. A randomized double blind placebo controlled trial of the effect of homocysteine- lowering therapy with folic acid on endothelial function in patients with coronary artery disease. J. Am. Coll. Cardiol. 2001; 37(7): 1858-63.
  26. van Oort F.V., Melse-Boonstra A., Brouwer I.A., Clarke R., West C.E., Katan M.B., Verhoef P. Folic acid and plasma homocysteine reduction in older adults: a dose-finding study. Am. J. Clin. Nutr. 2003; 77(5): 1318-23.
  27. Neal B., MacMahon S., Ohkubo T., Tonkin A., Wilcken D., for the Pacific Study Group. Dose-dependent effects of folic acid on plasma homocysteine in a randomised trial conducted among 723 individuals with coronary heart disease. Eur. Heart J. 2002; 23(19): 1509-15.
  28. Rydlewicz A., Simpson J.A., Taylor R.J., Bond C.M., Golden M.H.N. The effect of folic acid supplementation on plasma homocysteine in an elderly population. Q. J. Med. 2002; 95(1): 27-35.
  29. Ward M., McNulty H., McPartlin J., Strain J.J., Weir D.G., Scott J.M. Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. Q. J. Med. 1997; 90(8): 519-24.
  30. Jacques P.F., Selhub J., Bostom A.G., Wilson P.W.F., Rosenberg I.H. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N. Engl. J. Med. 1999; 340(19): 1449-54.
  31. Toole J.F., Malinow M.R., Chambless L.E., Spence J.D., Pettigrew L.C., Howard V.J. et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004; 291(5): 565-75.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies