Associations of Serum Folate and Vitamin B12 Levels With Cardiovascular Disease Mortality Among Patients With Type 2 Diabetes

Importance The associations of serum folate and vitamin B 12 levels with cardiovascular outcomes among patients with type 2 diabetes (T2D) remain unclear. Objective To investigate the associations of serum folate and vitamin B 12 levels with risk of cardiovascular disease (CVD) mortality among individuals with T2D. Design, Setting, and Participants This prospective cohort study included 8067 patients with T2D who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 through 2014 and NHANES III (1988-1994). American Diabetes Association criteria were used to define T2D. Data were analyzed between October 1, 2020, and April 1, 2021. Exposures Serum folate and vitamin B 12 levels. Main Outcomes and Measures Multivariable Cox proportional hazards regression models were used to compute hazard ratios and 95% CIs for the associations of serum folate and vitamin B 12 levels with risks of CVD and all-cause mortality. Two multivariable models were constructed. Restricted cubic spline analyses were used to examine the nonlinear association of serum folate levels and vitamin B 12 levels with CVD mortality, and nonlinearity was assessed using the likelihood ratio test. Results This cohort study included data from 7700 participants in the folate analysis (mean [SE] age, 57.8 [0.3] years; 3882 women [weighted, 50.5%]; median serum folate level, 12.1 ng/mL [IQR, 7.1-19.5 ng/mL]) and 4860 participants for the vitamin B 12 analysis (mean [SE] age, 57.8 [0.3] years; 2390 men [weighted, 50.7%]; median serum vitamin B 12 level, 506.1 pg/mL [IQR, 369.1-703.5 pg/mL]). During 72 031 person-years of follow-up, 799 CVD deaths were documented for the folate analysis, and during 43 855 person-years of follow-up, 467 CVD deaths were reported for the vitamin B 12 analysis. Nonlinear associations were observed for serum levels of folate ( P = .04 for nonlinearity) and vitamin B 12 ( P = .04 for nonlinearity) with risk of CVD mortality among patients with T2D. Compared with participants in the second quartile of serum folate levels (7.1-12.1 ng/mL), the hazard ratios for CVD mortality were 1.43 (95% CI, 1.04-1.98) for participants in the lowest serum folate level quartile (<7.1 ng/mL) and 1.03 (95% CI, 0.74-1.44) for participants in the highest quartile (≥19.5 ng/mL). In addition, compared with participants in the second quartile of serum vitamin B 12 levels (369.1-506.0 pg/mL), the hazard ratios for CVD mortality were 1.74 (95% CI, 1.20-2.52) for participants in the lowest quartile (<369.1 pg/mL) and 2.32 (95% CI, 1.60-3.35) for participants in the highest quartile (≥703.5 pg/mL). Similar patterns of association were observed for all-cause mortality (nonlinearity: P = .01 for folate and P = .02 for vitamin B 12 ). Conclusions and Relevance This cohort study found that both low and high serum levels of vitamin B 12 as well as low serum levels of folate were significantly associated with higher risk of CVD mortality among individuals with T2D.