Optimal folic acid dosage in lowering homocysteine: Precision Folic Acid Trial to lower homocysteine (PFAT-Hcy)

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Abstract

Background

While folic acid (FA) is widely used to treat elevated total homocysteine (tHcy), promoting vascular health by reducing vascular oxidative stress and modulating endothelial nitric oxide synthase, the optimal daily dose and individual variation by MTHFR C677T genotypes have not been well studied. Therefore, this study aimed to explore the efficacy of eight different FA dosages on tHcy lowering in the overall sample and by MTHFR C677T genotypes.

Methods

This multicentered, randomized, double-blind, controlled clinical trial included 2697 eligible hypertensive adults with elevated tHcy (≥ 10 mmol/L) and without history of stroke and cardiovascular disease. Participants were randomized into eight dose groups of FA combined with 10 mg enalapril maleate, taken daily for 8 weeks of treatment.

Results

The intent to treat analysis included 2163 participants. In the overall sample, increasing FA dosage led to steady tHcy reduction within the FA dosing range of 0–1.2 mg. However, a plateau in tHcy lowering was observed in FA dose range of 1.2–1.6 mg, indicating a ceiling effect. In contrast, FA doses were positively and linearly associated with serum folate levels without signs of plateau. Among MTHFR genotype subgroups, participants with the TT genotype showed greater efficacy of FA in tHcy lowering.

Conclusions

This randomized trial lent further support to the efficacy of FA in lowering tHcy; more importantly, it provided critically needed evidence to inform optimal FA dosage. We found that the efficacy of FA in lowering tHcy reaches a plateau if the daily dosage exceeds 1.2 mg, and only has a small gain by increasing the dosage from 0.8 to 1.2 mg.

ClinicalTrials.gov Identifier

NCT03472508 (Registration Date: March 21, 2018).

Supplementary Information

The online version contains supplementary material available at 10.1007/s00394-024-03344-8.

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Most cited references 42

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The Epidemiology of Global Micronutrient Deficiencies

Regan L. Bailey, Keith P. West Jr, Robert E Black (2015)

Micronutrients are essential to sustain life and for optimal physiological function. Widespread global micronutrient deficiencies (MNDs) exist, with pregnant women and their children under 5 years at the highest risk. Iron, iodine, folate, vitamin A, and zinc deficiencies are the most widespread MNDs, and all these MNDs are common contributors to poor growth, intellectual impairments, perinatal complications, and increased risk of morbidity and mortality. Iron deficiency is the most common MND worldwide and leads to microcytic anemia, decreased capacity for work, as well as impaired immune and endocrine function. Iodine deficiency disorder is also widespread and results in goiter, mental retardation, or reduced cognitive function. Adequate zinc is necessary for optimal immune function, and deficiency is associated with an increased incidence of diarrhea and acute respiratory infections, major causes of death in those <5 years of age. Folic acid taken in early pregnancy can prevent neural tube defects. Folate is essential for DNA synthesis and repair, and deficiency results in macrocytic anemia. Vitamin A deficiency is the leading cause of blindness worldwide and also impairs immune function and cell differentiation. Single MNDs rarely occur alone; often, multiple MNDs coexist. The long-term consequences of MNDs are not only seen at the individual level but also have deleterious impacts on the economic development and human capital at the country level. Perhaps of greatest concern is the cycle of MNDs that persists over generations and the intergenerational consequences of MNDs that we are only beginning to understand. Prevention of MNDs is critical and traditionally has been accomplished through supplementation, fortification, and food-based approaches including diversification. It is widely accepted that intervention in the first 1,000 days is critical to break the cycle of malnutrition; however, a coordinated, sustainable commitment to scaling up nutrition at the global level is still needed. Understanding the epidemiology of MNDs is critical to understand what intervention strategies will work best under different conditions.

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American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism

Thomas L Ortel, Ignacio Neumann, Walter Ageno … (2020)

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), occurs in ∼1 to 2 individuals per 1000 each year, corresponding to ∼300 000 to 600 000 events in the United States annually. These evidence-based guidelines from the American Society of Hematology (ASH) intend to support patients, clinicians, and others in decisions about treatment of VTE. ASH formed a multidisciplinary guideline panel balanced to minimize potential bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and adult patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment. The panel agreed on 28 recommendations for the initial management of VTE, primary treatment, secondary prevention, and treatment of recurrent VTE events. Strong recommendations include the use of thrombolytic therapy for patients with PE and hemodynamic compromise, use of an international normalized ratio (INR) range of 2.0 to 3.0 over a lower INR range for patients with VTE who use a vitamin K antagonist (VKA) for secondary prevention, and use of indefinite anticoagulation for patients with recurrent unprovoked VTE. Conditional recommendations include the preference for home treatment over hospital-based treatment for uncomplicated DVT and PE at low risk for complications and a preference for direct oral anticoagulants over VKA for primary treatment of VTE.

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Homocysteine lowering with folic acid and B vitamins in vascular disease.

Eva Lonn, Salim Yusuf, Malcolm Arnold … (2006)

In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease. We randomly assigned 5522 patients 55 years of age or older who had vascular disease or diabetes to daily treatment either with the combination of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or with placebo for an average of five years. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, and stroke. Mean plasma homocysteine levels decreased by 2.4 micromol per liter (0.3 mg per liter) in the active-treatment group and increased by 0.8 micromol per liter (0.1 mg per liter) in the placebo group. Primary outcome events occurred in 519 patients (18.8 percent) assigned to active therapy and 547 (19.8 percent) assigned to placebo (relative risk, 0.95; 95 percent confidence interval, 0.84 to 1.07; P=0.41). As compared with placebo, active treatment did not significantly decrease the risk of death from cardiovascular causes (relative risk, 0.96; 95 percent confidence interval, 0.81 to 1.13), myocardial infarction (relative risk, 0.98; 95 percent confidence interval, 0.85 to 1.14), or any of the secondary outcomes. Fewer patients assigned to active treatment than to placebo had a stroke (relative risk, 0.75; 95 percent confidence interval, 0.59 to 0.97). More patients in the active-treatment group were hospitalized for unstable angina (relative risk, 1.24; 95 percent confidence interval, 1.04 to 1.49). Supplements combining folic acid and vitamins B6 and B12 did not reduce the risk of major cardiovascular events in patients with vascular disease. (ClinicalTrials.gov number, NCT00106886; Current Controlled Trials number, ISRCTN14017017.). Copyright 2006 Massachusetts Medical Society.

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Author and article information

Contributors

Xiaoshu Cheng: xiaoshumenfan@126.com

Journal

Journal ID (nlm-ta): Eur J Nutr

Journal ID (iso-abbrev): Eur J Nutr

Title: European Journal of Nutrition

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 1436-6207

ISSN (Electronic): 1436-6215

Publication date (Electronic): 13 March 2024

Publication date PMC-release: 13 March 2024

Publication date (Print): 2024

Volume: 63

Issue: 5

Pages: 1513-1528

Affiliations

[1 ]Department of Cardiology, The Second Affiliated Hospital, Jiangxi medical College, Nanchang University, ( https://ror.org/042v6xz23) Nanchang, China

[2 ]Center for Prevention and Treatment of Cardiovascular Diseases, The Second Affiliated Hospital of Nanchang University, ( https://ror.org/01nxv5c88) Nanchang, China

[3 ]Biological Anthropology, University of California Santa Barbara, ( https://ror.org/02t274463) Santa Barbara, CA USA

[4 ]Institute of Biomedicine, Anhui Medical University, ( https://ror.org/03xb04968) Hefei, China

[5 ]Graduate School at Shenzhen, Tsinghua University, ( https://ror.org/03cve4549) Shenzhen, China

[6 ]Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, ( https://ror.org/04v3ywz14) Beijing, China

[7 ]Department of Cardiology, Peking University First Hospital, ( https://ror.org/02z1vqm45) Beijing, China

[8 ]College of Pharmacy, Jinan University, ( https://ror.org/02xe5ns62) Guangzhou, China

[9 ]The Department of Nephrology, The University of Hongkong-Shenzhen Hospital, ( https://ror.org/01me2d674) Shenzhen, China

[10 ]GRID grid.284723.8, ISNI 0000 0000 8877 7471, National Clinical Research Study Center for Kidney Disease, The State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, , Southern Medical University, ; Guangzhou, China

[11 ]Department of Hypertension, Heart Center, Peking University People’s Hospital, ( https://ror.org/035adwg89) Beijing, China

[12 ]School of Health Administration, Anhui Medical University, ( https://ror.org/03xb04968) Hefei, China

[13 ]Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, ( https://ror.org/00za53h95) Baltimore, USA

[14 ]Centers for Metabolic Disease Research, Cardiovascular Research and Thrombosis Research, Temple University, Lewis Katz School of Medicine, ( https://ror.org/00kx1jb78) Philadelphia, PA USA

Author information

Xiao Huang http://orcid.org/0000-0003-0686-6318

Article

Publisher ID: 3344

DOI: 10.1007/s00394-024-03344-8

PMC ID: 11329420

PubMed ID: 38478042

SO-VID: 5e72e407-f406-4dd4-b6d9-8cd3f8f7b2b1

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 21 September 2023

Date accepted : 23 January 2024

Funding

Funded by: the National Natural Science Foundation of China

Award ID: 81960074

Award Recipient : Xiao Huang

Funded by: Key R&D Projects, Jiangxi

Award ID: 20203BBGL73173

Award Recipient : Xiao Huang

Funded by: Key R&D Plan-Key Projects

Award ID: 20212BBG71012

Award Recipient : Xiao Huang

Funded by: the Jiangxi Provincial Health Commission

Award ID: 202130440

Award Recipient : Xiao Huang

Funded by: the Jiangxi Science and Technology Innovation Platform Project

Award ID: 20165BCD41005

Award Recipient : Xiaoshu Cheng

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ScienceOpen disciplines: Nutrition & Dietetics

Keywords: folic acid,homocysteine,mthfr c677t genotypes,optimal dosage

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ScienceOpen disciplines: Nutrition & Dietetics

Keywords: folic acid, homocysteine, mthfr c677t genotypes, optimal dosage

Optimal folic acid dosage in lowering homocysteine: Precision Folic Acid Trial to lower homocysteine (PFAT-Hcy)

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Abstract

Background

Methods

Results

Conclusions

ClinicalTrials.gov Identifier

Supplementary Information

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Karger: Nutrition and Dietetics

Most cited references 42

The Epidemiology of Global Micronutrient Deficiencies

American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism

Homocysteine lowering with folic acid and B vitamins in vascular disease.

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