Semin Thromb Hemost 2000; Volume 26(Number 03): 341-348
DOI: 10.1055/s-2000-8101
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Vitamin Supplements and Cardiovascular Risk: Review of the Randomized Trials of Homocysteine-Lowering Vitamin Supplements

ROBERT. CLARKE, JANE. ARMITAGE
  • Radcliffe Infirmary, Oxford, England
Further Information

Publication History

Publication Date:
31 December 2000 (online)

ABSTRACT

Epidemiological studies have shown that higher blood homocysteine levels appear to be associated with higher risks of coronary, cerebral, and peripheral vascular disease and are inversely related to blood levels of folate and of vitamin B 12 and vitamin B6. However, observational studies cannot exclude the possibility that elevated homocysteine levels may be associated with some other factor, rather than being causally related to vascular disease. Large-scale clinical trials of sufficient dose and duration of treatment are required to test this hypothesis, but there was substantial uncertainty about the optimal vitamin regimen to test in such trials. A meta-analysis of 12 randomized trials of vitamin supplements to lower homocysteine levels was carried out to determine the optimal dose of folic acid required to lower homocysteine levels and to assess whether vitamin B 12 or vitamin B6 had additive effects. This meta-analysis demonstrated that reductions in blood homocysteine levels were greater at higher pretreatment blood homocysteine levels and at lower pretreatment folate concentrations. After standardization for a pretreatment homocysteine concentration of 12 μmol/L and folate concentration of 12 nmol/L (approximate average concentrations for western populations), dietary folic acid reduced homocysteine levels by 25% (95% confidence interval [CI]: 23 to 28%) with similar effects in a daily dosage range of 0.5 to 5 mg. Vitamin B 12 (mean 0.5 mg) produced an additional reduction in blood homocysteine of 7%, whereas vitamin B 6 (mean 16.5 mg) did not have any significant effect. Hence, in typical populations, daily supplementation with both 0.5 to 5 mg folic acid and about 0.5 mg vitamin B 12 would be expected to reduce homocysteine levels by one quarter to one third (from about 12 μmol/L to about 8 to 9 μmol/L). Large-scale randomized trials of such regimens are now required to determine whether lowering homocysteine levels by folic acid and vitamin B 12, with or without added vitamin B6, reduces the risk of vascular disease.

REFERENCES

  • 1 Boushey C, Beresford S AA, Omenn G S, Motulsky A G. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes.  JAMA . 1995;  274 1049-1057
  • 2 Danesh J, Lewington S. Plasma homocysteine and coronary heart disease.  J Cardiovasc Risk . 1998;  5 229-232
  • 3 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 2693-2698
  • 4 Finch S, Doyle W, Lowe C. National Diet and Nutrition Survey: People aged 65 years and over. Vol. 1: Report of the diet and nutrition survey London: HMSO 1998
  • 5 Homocysteine Lowering Trialist's Collaboration.  Lowering blood homocysteine with folic acid based supplements: Meta-analysis of randomised trials. BMJ . 1998;  316 894-898
  • 6 Landgren F, Israelsson B, Lindgren A. Plasma homocysteine in acute myocardial infarction: Homocysteine-lowering effect of folic acid.  J Intern Med . 1995;  237 381-388
  • 7 den Heijer M, Brouwer I A, Bos G MJ. Vitamin supplementation reduces blood homocysteine levels: A controlled trial in patients with venous thrombosis and healthy volunteers.  Arterioscl Thromb Vasc Biol . 1998;  18 356-361
  • 8 Ubbink J B, Vermaak W JH, van der Merwe A. Vitamin requirements for the treatment of hyperhomocysteinemia in humans .  J Nutr . 1994;  124 1927-1933
  • 9 Ubbink J B, van der Merwe A, Vermaak W JH, Delport R. Hyperhomocysteinemia and the response to vitamin supplementation.  Clinical Invest . 1993;  71 993-998
  • 10 Naurath H J, Joosten E, Riezler R. Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations.  Lancet . 1995;  346 85-89
  • 11 Dierkes J. Vitamin requirements for the reduction of homocysteine blood levels in healthy young women. University of Bonn; 1995. Ph.D. thesis
  • 12 Woodside J V, Yarnell J WG, Young I S. The effects of oral vitamin supplementation on cardiovascular risk factors .  Proc Nutr Soc . 1997;  56 149
  • 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
  • 14 Saltzman E, Mason J B, Jacques P F. B vitamin supplementation lowers homocysteine levels in heart disease .  Clin Res . 1994;  42 172
  • 15 Stabler S P, Allen R H, Savage D G, Lindenbaum J. Clinical spectrum and diagnosis of cobalamin deficiency.  Blood . 1990;  76 871-881
  • 16 Savage D G, Lindenbaum J. Folate-cobalamin interactions. In: Folate in Health and Disease. Bailey LB, ed New York: Marcel Dekker Inc, 1995: 237-285
  • 17 Lindenbaum J, Healton E B, Savage D G. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis.  N Engl J Med . 1988;  318 1720-1728
  • 18 Cambell N RC. How safe are folic acid supplements?.  Arch Intern Med . 1996;  156 1638-1644
  • 19 Bostom A G, Jacques P F, Nadeau M R. Postmethionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: Initial results from the NHLBI Family Heart Study .  Atherosclerosis . 1995;  116 147-151
  • 20 MacMahon S, Peto R, Cutler J. Blood pressure, stroke and coronary heart disease; prolonged differences in blood pressure; prospective observational studies corrected for regression dilution bias.  Lancet . 1990;  335 765-774
  • 21 Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Study (4S).  Lancet . 1994;  344 1383-1389
  • 22 Sacks F M, Pfeffer M A, Moye L A. The effects of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.  N Engl J Med . 1996;  335 1001-1009
  • 23 Shepherd J, Cobbe S M, Ford I. For the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolaemia .  N Engl J Med . 1995;  333 1301-1307
  • 24 Robinson K, Arheart K, Refsum H. Low circulating folate and vitamin B6 concentrations: Risk factors for stroke, peripheral vascular disease, and coronary artery disease.  Circulation. . 1998;  97 437-443
  • 25 Rimm E B, Willett W C, Hu F B. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women.  JAMA . 1998;  279 359-364
  • 26 Peto R, Doll R, Buckley J D, Sporn M B. Can dietary beta-carotene materially reduce human cancer rates?.  Nature . 1981;  290 201-208
  • 27 Hennekens C H, Buring J E, Manson J M. Lack of effect of long-term supplementation with beta-carotene on the incidence of malignant neoplasms and cardiovascular disease.  N Engl J Med . 1996;  334 1145-1149
  • 28 Alpha-Tocopherol, Beta-carotene Cancer Prevention Study Group. The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers.  N Engl J Med . 1994;  330 1029-1035
  • 29 Omenn G S, Goodman G E, Thornquist M D. Effects of a combination of beta-carotene and vitamin A on lung cancer and cardiovascular disease.  N Engl J Med . 1996;  334 1150-1155
    >