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Homocysteine and vascular disease: review of published results of the homocysteine-lowering trials

  • Homocysteine and B-Vitamin Metabolism
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Moderately elevated homocysteine levels have been associated with a higher risk of cardiovascular disease in observational studies, but whether these associations are causal is uncertain. Randomized trials of dietary supplementation with B vitamins were set up to assess whether lowering homocysteine levels could reduce the risk of vascular disease. This review is based on a meta-analysis of published results of eight homocysteine-lowering trials for preventing vascular disease. The eight trials comprised a total of 37,485 individuals and provided comparisons of the effects of B vitamins on 5,074 coronary heart disease (CHD) events, 1,483 stroke events, 2,692 incident cancer events, and 5,128 deaths. Our meta-analysis assessed the effects of lowering homocysteine levels by about 25% for about 5 years. Allocation to B vitamins had no beneficial effects on any cardiovascular events, with hazard ratios (95% confidence intervals) of 1.01 (0.96–1.07) for CHD and 0.96 (0.87–1.07) for stroke. Moreover, allocation to B vitamins had no significant adverse effects on cancer [1.08 (0.99–1.17)], or for death from any cause [1.02 (0.97–1.07)]. Thus, supplementation with B vitamins had no statistically significant effects on the risks of cardiovascular events, total mortality rates, or cancer. A meta-analysis based on individual participant data from all available trials will assess the effects of lowering homocysteine levels on a broader range of outcomes, overall and in all relevant subgroups. However, available evidence does not support the routine use of B vitamins to prevent cardiovascular disease.

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Abbreviations

CHD:

coronary heart disease

HR:

hazard ratio

References

  • Albert CM, Cook NR, Gaziano JM, Zaharris E, MacFadyen J, Danielson E et al (2008) Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA 299(17):2027–2036

    Article  CAS  PubMed  Google Scholar 

  • Baker F, Picton D, Blackwood S, Hunt J, Erskine M, Dyas M et al (2002) Blinded comparison of folic acid and placebo in patients with ischaemic heart disease: an outcome trial. Circulation 106:3642, abst

    Google Scholar 

  • Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, Wang H, Nordrehaug JE, Arnesen E, Rasmussen K, NORVIT Trial Investigators (2006) Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction. N Engl J Med 354(15):1578–1588

    Article  CAS  PubMed  Google Scholar 

  • Bostom AG, Carpenter MA, Hunsicker L, Jacques PF, Kusek JW, Levey AS et al (2009) Baseline characteristics of participants in the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial. Am J Kidney Dis 53(1):121–128

    Article  PubMed  Google Scholar 

  • Boushey CJ, Beresford SA, Omenn GS, Motulsky AG (1995) A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 274(13):1049–1057

    Article  CAS  PubMed  Google Scholar 

  • B-Vitamin Treatment Trialists’ Collaboration (2006) Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Am Heart J 151(2):282–287

    Article  Google Scholar 

  • Carson NA, Cusworth DC, Dent CE, Field CM, Neill DW, Westall RG (1963) Homocystinuria: a new inborn error of metabolism associated with mental deficiency. Arch Dis Child 38:425–436

    Article  CAS  PubMed  Google Scholar 

  • Clarke R, Daly L, Robinson K, Naughten E, Cahalane S, Fowler B et al (1991) Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 324(17):1149–1155

    Article  CAS  PubMed  Google Scholar 

  • Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE et al (2010) Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer and cause-specific mortality: meta-analysis of 8 randomized trials involving 37485 individuals. Arch Int Med 170:1622–1630

    Article  CAS  Google Scholar 

  • Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS et al (2007) Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 297(21):2351–2359

    Article  CAS  PubMed  Google Scholar 

  • Danesh J, Lewington S (1998) Plasma homocysteine and coronary heart disease: systematic review of published epidemiological studies. J Cardiovasc Risk 5(4):229–232

    Article  CAS  PubMed  Google Scholar 

  • Early Breast Cancer Trialists’ (CTT) Collaborative Group (1990) Treatment of early breast cancer. Vol 1 Worldwide evidence 1985-1990. Oxford University Press, Oxford

    Google Scholar 

  • Ebbing M, Bleie O, Ueland PM, Nordrehaug JE, Nilsen DW, Vollset SE et al (2008) Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial. JAMA 300(7):795–804

    Article  CAS  PubMed  Google Scholar 

  • Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS et al (2009) Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst 101(6):432–435

    Article  CAS  PubMed  Google Scholar 

  • Galan P, Briancon S, Blacher J, Czernichow S, Hercberg S (2008) The SU.FOL.OM3 Study: a secondary prevention trial testing the impact of supplementation with folate and B-vitamins and/or Omega-3 PUFA on fatal and non fatal cardiovascular events, design, methods and participants characteristics. Trials 9:35

    Article  PubMed  Google Scholar 

  • Gerritsen T, Vaughn JG, Waisman HA (1962) The identification of homocystine in the urine. Biochem Biophys Res Commun 9:493–496

    Article  CAS  PubMed  Google Scholar 

  • Giovannucci E (2002) Epidemiologic studies of folate and colorectal neoplasia: a review. J Nutr 132(8 Suppl):2350S–2355S

    CAS  PubMed  Google Scholar 

  • Hankey GJ, Algra A, Chen C, Wong MC, Cheung R, Wong L et al (2007) VITATOPS, the Vitamins to prevent stroke trial: rationale and design of a randomised trial of B-vitamin therapy in patients with recent transient ischaemic attack or stroke. Int J Stroke 2(2):144–150

    Article  CAS  PubMed  Google Scholar 

  • Homocysteine Lowering Trialists’ Collaboration (2005) Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr 82(4):806–812

    Google Scholar 

  • Homocysteine Studies Collaboration (2002) Homocysteine and risk of ischemic heart disease and stroke a meta-analysis. JAMA 288:2015–2022

    Article  Google Scholar 

  • Jamison RL, Hartigan P, Kaufman JS, Goldfarb DS, Warren SR, Guarino PD et al (2007) Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA 298(10):1163–1170

    Article  CAS  PubMed  Google Scholar 

  • Kim YI (2004) Will mandatory folic acid fortification prevent or promote cancer? Am J Clin Nutr 80(5):1123–1128

    CAS  PubMed  Google Scholar 

  • Larsson SC, Giovannucci E, Wolk A (2007) Folate and risk of breast cancer: a meta-analysis. J Natl Cancer Inst 99(1):64–76

    Article  CAS  PubMed  Google Scholar 

  • Lin J, Lee IM, Cook NR, Selhub J, Manson JE, Buring JE et al (2008) Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women. Am J Clin Nutr 87(3):734–743

    CAS  PubMed  Google Scholar 

  • Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, Sheridan P, Pogue J et al (2006) Homocysteine lowering with folic acid and B-vitamins in vascular disease. N Engl J Med 354:1567–1577

    Article  CAS  PubMed  Google Scholar 

  • Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G et al (2007) A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomark Prev 16(7):1325–1329

    Article  CAS  Google Scholar 

  • McCully KS (1969) Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56(1):111–128

    CAS  PubMed  Google Scholar 

  • Mudd SH, Finkelstein JD, Irreverre F, Laster L (1964) Homocystinuria: an enzymatic defect. Science 143:1443–1445

    Article  CAS  PubMed  Google Scholar 

  • Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, Andria G, Boers GH, Bromberg IL, Cerone R et al (1985) The natural history of homocystinuria due to cystathionine β-synthase deficiency. Am J Hum Genet 37:1–31

    CAS  PubMed  Google Scholar 

  • Mudd SH, Levy HL, Skovby F (1989) Disorders of transulfuration. In: Schriver CF, Baudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease. McGraw Hill, New York, pp 693–734

    Google Scholar 

  • Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH) Collaborative Group (2010) Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA 303:2486–2494

    Article  Google Scholar 

  • Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ et al (2004) 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 291(5):565–575

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Qin X, Demirtas H, Li J, Mao G, Huo Y et al (2007) Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 369(9576):1876–1882

    Article  CAS  PubMed  Google Scholar 

  • Wilcken DEL, Wilcken B (1976) The pathogenesis of coronary artery disease: a possible role for methionine metabolism. J Clin Invest 57:1079–1082

    Article  CAS  PubMed  Google Scholar 

  • Yang Q, Botto LD, Erickson JD, Berry RJ, Sambell C, Johansen H et al (2006) Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation 113(10):1335–1343

    Article  PubMed  Google Scholar 

  • Yap S, Boers GH, Wilcken B, Wilcken DE, Brenton DP, Lee PJ et al (2001) Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study. Arterioscler Thromb Vasc Biol 21(12):2080–2085

    Article  CAS  PubMed  Google Scholar 

  • Yusuf S, Collins R, Peto R, Furberg C, Stampfer MJ, Goldhaber SZ, Hennekens CH (1985) Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side-effects from 33 randomized controlled trials. Eur Heart J 6(7):556–585

    CAS  PubMed  Google Scholar 

  • Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD et al (2003) Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst 95(5):373–380

    Article  CAS  PubMed  Google Scholar 

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Details of funding

This work was supported by the British Heart Foundation and Medical Research Council.

Competing interest statement

The authors confirm independence of the sponsors; the content of the article has not been influenced by the sponsors. The Clinical Trial Service Unit has a policy of staff not accepting fees or honoraria.

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Authors and Affiliations

  1. Clinical Trial Service Unit and Epidemiological Studies Unit, University of Oxford, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford, OX3 7LF, UK

    Robert Clarke, Jim Halsey, Derrick Bennett & Sarah Lewington

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  1. Robert Clarke
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  2. Jim Halsey
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  3. Derrick Bennett
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  4. Sarah Lewington
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Corresponding author

Correspondence to Robert Clarke.

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Communicated by: Viktor Kozich

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Clarke, R., Halsey, J., Bennett, D. et al. Homocysteine and vascular disease: review of published results of the homocysteine-lowering trials. J Inherit Metab Dis 34, 83–91 (2011). https://doi.org/10.1007/s10545-010-9235-y

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  • DOI: https://doi.org/10.1007/s10545-010-9235-y

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