Folic acid supplementation and serum trimethylamine oxide (TMAO) lowering: new insight from the post hoc analysis of Precision Folic Acid Trial to lower homocysteine (PFAT-Hcy)

Background: The impact of folic acid supplementation on trimethylamine oxide (TMAO) levels in hypertensive patients have not been well-studied. This study sought to investigate the association between folic acid supplementation in a range of doses and corresponding change in serum TMAO levels among Chinese hypertensive patients. Methods: This is a post hoc analysis of 1562 hypertensive patients from Precision Folic Acid Trial to lower homocysteine (PFAT-Hcy) who were randomly assigned to one of eight folic acid daily treatment groups ranging from 0 to 2.4 mg (0, 0.4, 0.6, 0.8, 1.2, 1.6, 2.0, 2.4 mg). The duration of the treatment was 8 weeks. The endpoint of this study was the reduction in TMAO levels by the end of 8-week treatment compared to the baseline level. Results: In the overall sample, as the dosage of folic acid supplementation escalated from 0 to 2.4 mg, there was no statistically significant association between folic acid supplementation and TMAO changes. However, subgroup analysis revealed that the association between folic acid supplementation and TMAO lowering differed by the baseline TMAO levels. When baseline TMAO was in the lowest tertile (<1.4 μmol/L) or the middle tertile (1.4–2.5 μmol/L), there was no association between folic acid supplementation and TMAO changes. However, among those with baseline TAMO in the highest tertile (>2.5 μmol/L), there was a significant inverse association between folic acid supplementation dosage and TMAO changes, the adjusted β (95% confidence interval [CI]) among those with the highest TMAO tertile was −0.58 (−1.10, −0.06); (P for interaction, 0.009). In this subgroup, we further observed that those with baseline elevated total homocysteine (tHcy) levels benefited even more from folic acid supplementation (P for interaction: 0.047). Conclusions: In this sample of Chinese adults with hypertension, folic acid supplementation can significantly lower serum TMAO levels in the subgroup with elevated serum TMAO levels (>2.5 μmol/L), and within this subgroup, those with concomitantly elevated tHcy benefited even more.