Folate Status and Mortality in US Adults With Diabetes: A Nationally Representative Cohort Study

Background: Public health concerns have gradually shifted from inadequate intakes to potential adverse effects associated with excessive folate intakes following the full implementation of mandatory folate fortification. This study aimed to examine the associations of red blood cell (RBC) folate with all-cause and cardiovascular disease (CVD) mortality among patients with diabetes.

Methods: Data of 15,514 adults aged 20 years or older, who participated in the National Health and Nutrition Examination Survey (1988-1994), were analyzed as the baseline examination. The participants were linked to mortality data from the survey date until December 31, 2015. The associations of RBC folate with all-cause and CVD mortality were examined using multivariable Cox regression models.

Results: During 297,708 person-years of follow-up (median of 19.2 years), 6,106 total deaths occurred, including 1,867 deaths from CVD, 1452 deaths from ischemic heart disease, and 415 deaths from stroke disease. The participants with the highest quartile of RBC folate had higher odds of diabetes (fully-adjusted odds ratio: 1.94 [95% CI: 1.53-2.48]). In Cox regression analyses, compared with the participants with the lowest quartile of RBC folate for diabetes, those from quartile 3 and quartile 4 had HRs (95% CIs) of 1.12 (0.87, 1.43) and 1.30 (1.04, 1.63) in all-cause mortality, respectively; in CVD mortality, the HRs were 1.73 (1.08, 2.76) and 1.47 (0.98, 2.22); in ischemic heart disease mortality, they were 2.01 (1.19, 3.39) and 1.62 (1.05, 2.50), respectively. However, high levels of RBC folate were negatively associated with all-cause mortality, CVD mortality and ischemic heart disease mortality in non-diabetes.

Conclusion: From the nationally representative data, increasing levels in RBC folate were independently associated with an increased risk of all-cause and CVD mortality among those diagnosed with diabetes, but high levels of RBC folate had a mild protective effect in non-diabetes. The underlying mechanism regarding folate and adverse outcomes in diabetes warrants further clarification.