Folic acid may be fine stuff in
its own way, but a panacea for cardiovascular disease
(CVD) it is not. That's the key finding of the largest
study on the subject to date, published in the December
13 issue of the Journal of the American Medical Association
(JAMA).
This meta-analysis of twelve different
studies cuts out the middleman that has so often complicated
our thinking on the relationship between folic acid
and CVD. That middleman is homocysteine, an amino acid
that is frequently found at elevated levels in the presence
of CVD.
We know that homocysteine levels
often seem to run in parallel to cardiovascular risk.
We also know that folic acid reduces homocysteine levels.
So it was natural to assume that taking folic acid would
reduce cardiovascular risk. Natural but wrong, it seems.
An example of this logic appeared
in the British Medical Journal in November. Reviewing
seven trials of folic acid and its effect on CVD, the
authors acknowledged that "If the only evidence available
were the trial results, we would still be in the dark."
But they go on to note that homocysteine appears linked
to CVD, and that folic acid reduces homocysteine. "It
follows that increasing folic acid consumption will
reduce the risk of heart attack and stroke by an amount
related to the homocysteine reduction achieved."
Not so, says Dr Lydia Bazzano,
of Tulane University in New Orleans, lead author of
the JAMA study. Her team's meta-analysis pooled
studies comprising a hefty 16,958 men and women with
existing renal or cardiovascular disease and studied
the effect of folic acid supplementation on CVD, heart
disease, stroke and all-cause mortality.
"It's fair to say that not only
was there no significant evidence of a protective effect,"
she says, "there was really no trend at all." The only
area in which there was any possible effect at all,
adds Dr Bazzano, was a nonsignificant reduction of stroke
risk in the higher-dose studies.
HOMOCYSTEINE
HOME-IN
Naturally, there are caveats. The most important is
that this was a study of secondary prevention in patients
whose age averaged about 62 and who already had disease.
There could still be a role in primary prevention in
younger patients, admits Dr Bazzano.
Another issue is the time of follow-up,
which was rarely more than five years and often as little
as two. But, says Dr Bazzano, "if anything, the largest
reduction in homocysteine levels was seen at the outset
of the studies, not towards the end."
A potential confounding factor
is that some of these studies took place in countries
like Canada where routine foodstuffs like bread and
milk are fortified with folic acid. But Dr Bazzano is
pretty confident that this factor was adequately controlled
for.
In any case, the studies did measure
the change in homocysteine levels, and these were very
significant. There's even less doubt than before that
folic acid reduces homocysteine concentrations. But
it had no apparent effect on CVD. In that sense, the
study is as much about homocysteine as it is about folic
acid. "It seems very possible that while homocysteine
runs in parallel to cardiovascular risk, it doesn't
cause it," says Dr Bazzano. Both could instead be independent
markers caused by some unknown underlying factor. If
that's so, then all the folic acid or folate in the
world may have no use in either primary or secondary
prevention.
None of this undermines the rationale
for folic acid fortification of our foods, which was
always about preventing birth defects, not CVD. And
in that it has been stunningly successful. Since Newfoundland
introduced folic acid into bread and milk, the province
has seen neural tube defects in newborns fall by over
80%.
Of course, in looking at all-cause
mortality, the JAMA study also had the potential
to find any hidden negative effect of taking such supplements.
There was none. "I think it's safe to say," says Dr
Bazzano, "that while we found no evidence of cardiovascular
benefit, we also pretty much ruled out any question
of harm."
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