Results of a longitudinal prospective cohort study were recently published in JAMA Network, detailing the associations between total B vitamin intake and incidence of metabolic syndrome (Met-S). This analysis used data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, comprised of an approximately equal number of black and white individuals (and men and women) aged 18-30 at recruitment, followed for a mean of 30 years. Met-S and its components were as defined by the American Heart Association and National Heart, Lung, and Blood Institute, and diet information was collected by a validated interviewer-administered diet history at baseline, year 7, and year 20, including assessment of both dietary and supplemental B vitamin intake. Assessment of B vitamin intake was limited to folate, B6, and B12.
After adjustment for potential confounders, a higher intake of all 3 B vitamins was associated with a lower incidence of Met-S. When comparing the highest to lowest quintiles of intake, folate, B6, and B12 were associated with a 61%, 39%, and 26% lower incidence of Met-S, respectively. Additionally, serum levels of each vitamin were significantly correlated to the estimated dietary intake, and also inversely associated with Met-S incidence. Comparing the highest to lowest quintiles of serum concentration, folate, B6, and B12 were associated with a 77%, 52%, and 30% lower incidence of Met-S, respectively. Furthermore, serum concentrations of each of these B vitamins were inversely related to homocysteine levels, which was itself associated with a greater Met-S incidence. Yet after adjusting for the decrease in homocysteine levels, there was still a significant reduction in Met-S incidence, indicating that the protection against Met-S is not likely to be entirely mediated through homocysteine reduction, but through multiple mechanisms.
These three B vitamins were also inversely associated with each of the components of Met-S. Folate intake was inversely associated with all components of Met-S, i.e., glucose, blood pressure, abdominal obesity, triglycerides, and low HDL-C. For example, those in the highest quintile of folate intake had a 75% lower incidence of low HDL-C, and a 53% lower incidence of elevated glucose. Vitamins B6 and B12 were both associated with a lower incidence of all Met-S components except glucose (and B12 was also not associated with blood pressure). For vitamin B12, a reduced incidence of Met-S was only observed among supplement users, suggesting a higher dosage may be necessary for the favorable association.
Consistent with previous NHANES observational data implying a protective effect of B vitamin intake on the risk for Met-S, the authors point out that there are also randomized and controlled, case-control, and cross-sectional studies that support this relationship, as well as biological plausibility. For instance, a meta-analysis of 22 randomized trials found that supplementation with folic acid reduced both systolic and diastolic blood pressure, and a previous meta-analysis of 12 studies found that it reduced both systolic and diastolic pressure, and also improved endothelial function. In patients with Met-S, folic acid supplementation has also been shown to improve several inflammatory markers, including hs-CRP, IL-6, and TNF-α. A previous publication from this same data set (CARDIA) suggested that higher folate intake was associated with a lower incidence of type 2 diabetes, possibly mediated by folate’s effects on insulin sensitivity, systemic inflammation, and homocysteine. Low levels of vitamin B12 and folate have both been associated with adiposity and dyslipidemia, and may potentially be another pathway improved by higher intakes. An inverse linear intake between B6 intake and cardiovascular disease has been observed in Korean men, but not women, though two large Chinese cohorts found an inverse relationship between intake and cardiovascular and all-cause mortality among both men and women.
One of the limitations of this study is, of course, its inability to determine causality, given that it is an observational study. Additionally, the authors point out that this study did not examine genetic risk factors that may modulate the influence of B vitamins on metabolic risk. Each of these B vitamins plays a role in one-carbon metabolism, and several genetic polymorphisms (such as MTHFR C677T) are clearly influenced by B vitamin intake and modify Met-S risk.
Not considered in this study was any potential role of riboflavin on Met-S or its components, which is an unfortunate limitation. Multiple threads of evidence point to riboflavin, particularly at levels achieved with supplementation, interacting with the MTHFR genotype to influence blood pressure and one-carbon such as S-adenosylmethionine and cystathionine. Riboflavin (in the form flavin adenine dinucleotide [FAD])is a cofactor for MTHFR, with previous studies indicating that blood pressure may be reduced 6-13 mmHG when supplementation is targeted to individuals with the MTHFR TT genotype, an effect greater than many anti-hypertensive medications. In a previous analysis of NHANES data, a lower risk for Met-S was observed with higher riboflavin intake, but this benefit maxed out at approximately 13mg/day. However, it seems highly likely that a targeted genotype-specific approach may provide substantially different outcomes.
Overall, this recent analysis provides the strongest observational evidence so far that B vitamin intake, even when controlled for relevant factors such as homocysteine and overall diet quality, is likely to provide protection against the development of Met-S.