Meta-analysis questions folic acid’s heart benefits

By Stephen Daniells

- Last updated on GMT

Related tags Folic acid Neural tube defects

Oxford researchers say reduced homocysteine levels don't reduce CV events
Oxford researchers say reduced homocysteine levels don't reduce CV events
Increased intakes of folic acid – a synthetic form of folate – may decrease blood levels of the amino acid homocysteine, but this does not translate into reductions in cardiovascular events, says a new meta-analysis from the University of Oxford.

The findings question the use of homocysteine as a marker for heart disease, with the meta-analysis of eight trials involving 37,485 participants showing no benefits on the risk of major vascular events, cancer, or deaths, despite reducing homocysteine levels by 25 per cent.

“Although the lack of any other benefits is disappointing (albeit fairly definitive), the lack of any significant adverse effects on vascular events, cancer incidence, cancer mortality and overall mortality provides reassurance about the safety of population-wide folic acid fortification,”​ wrote the Oxford-based researchers in the Archives of Internal Medicine​.

B for baby benefits

An overwhelming body of evidence links folate deficiency in early pregnancy to increased risk of neural tube defects (NTDs) - most commonly spina bifida and anencephaly - in infants. Most NTDs occur within the first 22 to 28 days of pregnancy, when the mother-to-be is not aware she is even pregnant.

Folic acid supplements after this time are too late to prevent neural tube defects and therefore fail to benefit women with unplanned pregnancies - more than half of all pregnancies in the US.

This connection led to the 1998 introduction of public health measures in the US and Canada, where all grain products are fortified with folic acid - the synthetic, bioavailable form of folate.

The benefits of folic acid have also been reported to extend to reducing homocysteine, which has been linked to heart disease. The link was founded on the observation that children with homocystinuria – a rare genetic condition causing extreme elevations in homocysteine levels – have higher rates of cardiovascular disease. Such an observation was therefore generalised to the wider population, with the hypothesis indicating that supplementation with B vitamins may reduce blood homocysteine levels and reduce the risk of heart disease.


Led by Professor Robert Clarke, the B-Vitamin Treatment Trialists' Collaboration analysed data from eight randomised trials completed before the end of 2009. Of the almost 38,000 participants, 18,723 received folic acid in doses ranging from 0.8 to 40 milligrams per day. The median length of the trials was five years.

The researchers document 9,326 major vascular events, 3,010 new cases of cancer, and 5,125 deaths. Despite a 25 per cent reduction in homocysteine levels in the folic acid recipients, there were no differences between folic acid and placebo for the risk of major heart or blood vessel events, said the researchers.

Furthermore, folic acid was not associated with a decrease (or increase) in the incidence of major coronary events, stroke, new cases of cancer, or death, added the researchers.

"Although some benefit might emerge with even longer treatment and follow-up, the trial results give no reason to expect this (particularly because cardiovascular benefits tend to emerge within just a few years with other cardioprotective treatments, such as antihypertensives or statins),”​ stated the researchers.

Still necessary for women

Commenting independently on the research, Ellen Mason, senior cardiac nurse for the UK charity, the British Heart Foundation, said folic acid remains necessary for women trying to conceive and in their first trimester because it reduces the chance of a neural tube defect such as spina bifida.

“Adding folic acid to bread in the US to reduce neural tube defects has not shown a significant reduction in heart attacks, strokes, or deaths from heart and circulatory disease, but it hasn’t caused any adverse increases in these conditions either, which is reassuring for the public,”​ she added.

Source: Archives of Internal Medicine
Volume 170, Number 18, Pages 1622-1631
“Effects of Lowering Homocysteine Levels With B Vitamins on Cardiovascular Disease, Cancer, and Cause-Specific Mortality”
Authors: R. Clarke, J. Halsey, S. Lewington, E. Lonn, J. Armitage, et al.

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