Does folic acid reduce stroke risk?

New studies offer evidence that may quell the dispute over the place of folic acid in stroke risk reduction. According to Rebecca Gottesman, MD, PhD, the current controversy over folic acid supplementation and stroke risk “most likely arises from the study designs of previous research,” rather than efficacy of the supplement.

Rebecca Gottesman“Prior studies had not demonstrated a benefit from folic acid supplementation in reducing risk of stroke, even among people who had already had a stroke, but that is probably because most of those studies were done in parts of the world where [dietary] folate supplementation is mandated,” said Gottesman, who is Johns Hopkins associate professor of Neurology and Epidemiology, Division of Cerebrovascular Neurology, and co-author and investigator of “Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China,” a study led by Y. Huo and published in the March 15 issue of JAMA.

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Why supplement?

Folic acid, or folate, a B vitamin, supports many bodily functions. Among other things, it is needed for DNA synthesis and repair, and is a key component in certain biological reactions. In human beings, it is essential to production of healthy red blood cells and prevention of anemia.

Because it cannot be synthesized by the human body, folic acid is used in many parts of the world to supplement essential food products such as grains. According to the National Center for Biotechnology Information, part of the National Institutes of Health, wheat-flour fortification is now mandated in 53 countries to reduce neural tube birth defect; China, however, has not yet implemented the policy.

Gottesman, citing stroke as the leading cause of death in China, described the study as “a large, randomized clinical trial among hypertensive adults in China."

She added, “This [research] demonstrated a clear benefit in stroke reduction in a population without folate supplementation, suggesting that folate might be very important in populations where folate is not supplemented, but also that individual genetic information might best guide not only treatment but prevention decisions.”  

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All in the design

Meir StampferAn editorial appearing concurrently in the JAMA issue supports Gottesman’s research.

In “Folate supplements for stroke prevention: Targeted trial trumps the rest,” Meir Stampfer, MD, DrPH, professor of Epidemiology and Nutrition at Harvard’s T.H. Chan School of Public Health, and colleague Walter Willett, MD, DrPh, of the same institution, also cited study design as the source of the folic acid/stroke controversy.

According to Stampfer, investigating the benefit of a supplement like folic acid “is very difficult in a culture where the population is most likely already consuming folate through their fortified diet.” Studies performed in the United States, he said, typically include individuals whose varying folate levels result from a fortified diet, a factor that will affect study outcomes.

In comparison, a randomized drug study is more controlled, said Stampfer.

“If you’re testing a drug, a statin for example, there are people who get a placebo, so they aren’t getting any drug. But if you’re testing an essential nutrient, there is no such thing as a ‘zero group’ - they’re all getting something.” In the study of an essential nutrient, "you have to compare something with something more," whereas a drug study "compares something with nothing." 

However, Stampfer continued, “It’s important to do this type of nutritional study, where dietary levels of intake are low, to test the hypothesis and help guide study design.” 

A meta-analysis

In 2012, the International Journal of Clinical Practice published “Efficacy of folic acid supplementation: New insight from a meta-analysis,” produced by a group also led by Y. Huo. The 2012 meta-analysis of randomized clinical trials investigated the effect and dosage of folic acid supplementation vs. the use of statins in reduction of stroke risk. 

According to Stampfer, this meta-analysis, which reported results from 55,784 study subjects participating in 15 out of 489 possible studies with stroke prevention as one of the endpoints, had probably provided “enough evidence to go forward with their latest reported investigation.”

The 2015 research, said Gottesman, “was designed to be sure that the two randomization groups were evenly matched by genotype and [that it] demonstrates a benefit overall, across all genotypes.”

The takeaway

The big message supports personalized medicine. “One treatment or preventive therapy may not be needed for everyone, but there may be certain individuals, even in countries with folate fortification, in whom there is a benefit of folic aid,” said Gottesman.

Stampfer agrees. “A lot of people in China, India, Africa - places with populations that have low folate - those people would benefit from fortification.” 

Barbara Hesselgrave is a freelance writer living in Baltimore.