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Research on Folic Acid

Elevated blood homocysteine concentration has been identified as an independent risk factor for cardiovascular disease (CVD), including diseases of the coronary, cerebral and peripheral vessels, and thromboembolism (Refsum et al. 1998). Folate serves as a coenzyme in the conversion of homocysteine to methionine and folate intake or status is inversely related to blood homocysteine concentrations (Riddell et al. 2000, Selhub et al. 1993, Verhoef et al. 1996).

Elevated blood homocysteine concentrations have been associated with an increased risk for coronary heart disease in cross-sectional and case-control studies, although less consistently in prospective studies (Christen et al. 2000). Supplementation with folic acid at doses ranging from 500 micrograms to 5 milligrams appear to uniformly lower homocysteine concentrations by approximately 25% (Homocysteine Lowering Trialists' Collaboration 1998).

Those with higher homocysteine concentrations or lower blood folate status appear to benefit the most from folic acid supplementation. A meta-analysis suggested that lowering homocysteine concentration by 3 micromoles/liter would result in a decrease in the risk of ischemic heart disease, deep vein thrombosis, and stroke of 16%, 25% and 24%, respectively (Wald et al. 2002).

Following mandatory folic acid fortification of enriched grain products in the U.S. in January 1998, a substantial increase in folate status has been observed in the national population (Centers for Disease Control and Prevention 2000) and select population groups (Choumenkovitch et al. 2001, Lawrence et al. 1999, Jacques et al. 1999). Similarly, decreases in homocysteine concentrations have been reported in the Framingham heart rate Offspring Study cohort (Jacques et al. 1999) and in patients with coronary artery disease (Anderson et al. 2004).

The long term impact of these changes on vascular disease risk in the U.S. population is not known, but could conceivably reduce the number of persons affected by vascular disease.
A key question is whether folic acid supplementation can reduce the risk for heart disease.

Observational data from the Nurses' Health Study indicate that total folate intakes of ≥393 micrograms/day from diet and supplements was associated with a 20-30% decreased risk for coronary heart disease in women (Rimm et al. 1998). A longitudinal study suggested that men in the highest quintile of folate intake (median 821 micrograms/day) had a ~30% reduced risk for ischemic stroke compared to men in the lowest quintile of intake (262 micrograms/day) (He et al. 2004). A similar observational study found no significant effect of higher folate intakes on stroke risk in women (Al-Delaimy et al. 2004).
Several randomized controlled trials have been conducted to determine if folic acid supplementation, with or without other B vitamins, can reduce the risk of heart disease or improve markers linked to heart health.

A meta-analysis including 14 randomized controlled trials evaluating the effect of folic acid supplementation on endothelial function indicated that folic acid improved flow mediated dilation by 1.08 percentage points over placebo (statistically significant). However, a meta-analysis of randomized controlled trials conducted between 1966 and 1996 evaluating folic acid supplementation on risk of CVD and all-cause mortality in subjects with pre-existing vascular disease reported no significant benefit (Bozzano et al. 2006).

A pooled analysis of trials on homocysteine lowering interventions using B vitamins reported no significant effect on non-fatal or fatal myocardial infarction, stroke, or death by any cause (Marti-Carvajal et al. 2009).

Despite overall substantial reductions in serum homocysteine ranging from 13% to 30% in randomized trials, only one study, the HOPE-2 trial, reported a significantly reduced risk of stroke with folic acid, vitamin B6 and vitamin B12 supplement taken for a median of 60 months (Ntaios et al. 2009).

A meta-analysis examining 13 randomized controlled trials to assess the efficacy for folic acid supplementation in the prevention of stroke indicated that folic acid did not demonstrate a major effect in averting stroke. However, there were mild benefits in primary stroke prevention (11% reduced risk) when folic acid was combined with other B vitamins and greater benefits were observed in trials with more male subjects (Lee et al. 2010).

Another meta-analysis including 14 trials concluded that folic acid supplementation did not affect primary cardiovascular clinical end points or stroke (Miller et al. 2010).  A meta-analysis using 10 randomized controlled trials (2025 subjects) was conducted to assess whether folic acid supplementation reduces the progression of atherosclerosis by measuring carotid intima-media thickness (CIMT). CIMT is an intermediate phenotype for early atherosclerosis. Results indicated that folic acid supplementation significantly reduced the progression of CIMT specifically in those with chronic kidney disease or high cardiovascular disease risk, but not in generally healthy individuals. This study underlines the importance of identifying specific populations that may benefit from folic acid supplementation (Qin et al. 2012).

A systematic review and meta-analysis examined 16 randomized controlled trials that included 44,841 subjects with major cardiovascular events, strokes, myocardial infarctions (MI), and cardiovascular-related deaths. Data revealed an 11% reduced risk of stroke with folic acid therapy, although the result was not statistically significant. There was no effect on the risk of MI with folic acid therapy. There was no evidence that folic acid therapy could reduce the risk for mortality or reduce the risk of other major cardiovascular events (Zhou et al. 2011).
A number of meta-analyses have been conducted to evaluate clinical trials and other studies related to the use of B vitamins for CVD risk reduction (Wang et al. 2007, Saposnik et al. 2009, Lee et al. 2010, Qin et al. 2012, Yang et al. 2012a, Ji et al. 2013). The most promising results relate to the reduced risk for stroke reported by some studies. A Cochrane Review of randomized controlled trials investigating the use of B vitamins to lower homocysteine reported on the results of 12 trials involving over 47,000 subjects. Compared to placebo, homocysteine-lowering interventions had no significant effect on myocardial infarction, stroke, or all-cause mortality (Martí-Carvajal et al. 2015). The overall conclusion was that the use of vitamin B6, folic acid, or vitamin B12 either alone or in combination is not supported for the prevention of cardiovascular events.

Trials conducted to date have failed to provide substantive support for folic acid in the primary prevention of cardiovascular disease. Factors related to study design and protocol, such as duration of intervention, lower baseline homocysteine concentrations due to folic acid fortification of the food supply, and the use of medications by study subjects that may have affected cardiovascular outcomes (e.g., statins, aspirin, and other lipid-lowering medications) may have underpowered the trials or confounded the results so that significant effects could not be detected (Debreceni and Debreceni 2014). The consensus remains that supplementation with B vitamins for CVD primary risk reduction is not warranted at this time.

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