Association of folic acid dosage with circulating unmetabolized folic acid in Chinese adults with H-type hypertension: a multicenter, double-blind, randomized controlled trial

Ping Chen; Linlin Tang; Yun Song; Binyan Wang; Xianhui Qin; Nan Zhang; Yaping Wei; Xiping Xu; Ziyi Zhou; Qiangqiang He; Lishun Liu; Sultan Mehmood Siddiqi; Xiao Huang; Xiaoshu Cheng; Genfu Tang; Yong Duan; Houqing Zhou; Jie Jiang; Sha Li

doi:10.3389/fnut.2023.1191610

Association of folic acid dosage with circulating unmetabolized folic acid in Chinese adults with H-type hypertension: a multicenter, double-blind, randomized controlled trial

Front Nutr. 2023 Sep 14:10:1191610. doi: 10.3389/fnut.2023.1191610. eCollection 2023.

Authors

Ping Chen¹, Linlin Tang², Yun Song³, Binyan Wang³, Xianhui Qin⁴, Nan Zhang⁴, Yaping Wei⁵, Xiping Xu⁵, Ziyi Zhou⁶, Qiangqiang He⁶, Lishun Liu⁷, Sultan Mehmood Siddiqi⁷, Xiao Huang⁸, Xiaoshu Cheng⁸, Genfu Tang⁹, Yong Duan¹⁰, Houqing Zhou¹¹, Jie Jiang¹, Sha Li¹

Affiliations

¹ College of Pharmacy, Jinan University, Guangzhou, China.
² State Key Laboratory of Natural Medicines, Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, China.
³ Institute of Biomedicine, Anhui Medical University, Hefei, China.
⁴ National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
⁵ Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, College of Food Sciences and Nutritional Engineering, China Agricultural University, Beijing, China.
⁶ Shenzhen Evergreen Medical Institute, Shenzhen, China.
⁷ Graduate School at Shenzhen, Tsinghua University, Shenzhen, China.
⁸ Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.
⁹ School of Health Administration, Anhui Medical University, Hefei, China.
¹⁰ Department of Clinical Laboratory, The First Affiliated Hospital of Kunming Medical University, Kunming, China.
¹¹ Department of Clinical Laboratory, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, China.

Abstract

Background: There is growing concern regarding elevated levels of circulating unmetabolized folic acid (UMFA) due to excessive intake of folic acid (FA). However, no randomized clinical trial has been conducted to examine the FA-UMFA dose-response relationship.

Objective: This study aimed to investigate the FA-UMFA dose-response relationship in Chinese adults with hypertension and elevated homocysteine (H-type hypertension), a population with clear clinical indication for FA treatment.

Methods: The data for this study were derived from a randomized, double-blind, multicenter clinical trial of 8 FA dosages on efficacy of homocysteine (Hcy) lowering. The parent trial had three 3 stages: screening period (2-10 days), run-in period (0-2 weeks, baseline visit), and double-blind treatment period (8 weeks) with follow-up visits at the end of the 2nd, 4th, 6th, and 8th weeks of treatment. Participants were randomly assigned to 8 treatment groups corresponding to FA dosages of 0, 0.4, 0.6, 0.8, 1.2, 1.6, 2.0 mg to 2.4 mg.

Results: This study included 1,567 Chinese adults aged ≥45 years with H-type hypertension. There was a positive but non-linear association between FA supplementation and UMFA levels in the dosage range of 0 mg to 2.4 mg. In the regression analysis, the coefficients for the linear and quadratic terms of FA dosage were both statistically significant (P < 0.001). Notably, the slope for UMFA was greater for FA dosages >0.8 mg (ß = 11.21, 95% CI: 8.97, 13.45) compared to FA dosages ≤0.8 mg (ß = 2.94, 95% CI: 2.59, 3.29). Furthermore, FA dosages higher than 0.8 mg did not confer additional benefits in terms of increasing 5-methyl tetrahydrofolic acid (5-MTHF, active form of folate) or reducing homocysteine (Hcy).

Conclusion: In Chinese adults with H-type hypertension, this study showed a positive, non-linear, dosage-response relationship between FA supplementation ranging from 0 to 2.4 mg and circulating UMFA levels. It revealed that 0.8 mg FA is an optimal dosage in terms of balancing efficacy (increasing 5-MTHF and lowering Hcy) while minimizing undesirable elevation of UMFA.

Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03472508?term=NCT03472508&draw=2&rank=1, identifier NCT03472508.

Keywords: H-type hypertension; dosage; folic acid; safety; unmetabolized folic acid.

Associated data

ClinicalTrials.gov/NCT03472508

Grants and funding

This study funding came from the Jiangxi Science and Technology Innovation Platform Project (20165BCD41005); Key R&D Projects, Jiangxi (20203BBGL73173); the Project of Jiangxi Provincial Health Commission (202130440); the Department of Science and Technology of Guangdong Province (2020B121202010); the Science, Technology and Innovation Committee of Shenzhen (JSGG20180703155802047 and JSGG20201103153807021); and the National Natural Science Foundation of China (81960074). None of the funding agencies participated in the study design; collection, management, analysis, and interpretation of the data; nor in the preparation, review, or approval of the manuscript.