High-Dose B Vitamin Supplementation and Progression of Subclinical Atherosclerosis: A Randomized Controlled Trial – Source: Stroke, Mar 1, 2009

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Background and Purpose: Although plasma total homocysteine (tHcy) levels are associated with cardiovascular disease, it remains unclear whether homocysteine is a cause or a marker of atherosclerotic vascular disease. We determined whether reduction of total homocysteine levels with B vitamin supplementation reduces subclinical atherosclerosis progression.

Methods: In this double-blind clinical trial, 506 participants 40 to 89 years of age with an initial total homocysteine greater than 8.5 µmol/L without diabetes and cardiovascular disease were randomized to:

• High-dose B vitamin supplementation (5 mg folic acid [B9] plus 0.4 mg vitamin B12 plus 50 mg vitamin B6 )

• Or matching placebo… for 3.1 years.

Subclinical atherosclerosis progression across 3 vascular beds was assessed using high-resolution B-mode ultrasonography to measure:

• Carotid artery intima media thickness (primary outcome) [Thickness of walls in artery supplying blood to the head and neck – strongly associated with plaque buildup/loss of flexibility.]

• And multidetector spiral CT to measure aortic and coronary artery calcium (secondary outcome).

Results: Although the overall carotid artery intima media thickness progression rate was lower with B vitamin supplementation than with placebo, statistically significant between-group differences were not found (P=0.31).


• Among subjects with baseline total homocysteine of 9.1 µmol/L or greater, those randomized to B vitamin supplementation had a statistically significant lower average rate of carotid artery intima media thickness progression compared with placebo (P=0.02);

• Among subjects with a baseline tHcy less than 9.1 µmol/L, there was no significant treatment effect (probability value for treatment interaction=0.02).

B vitamin supplementation had no effect on progression of aortic or coronary artery calcification overall or within subgroups.


High-dose B vitamin supplementation significantly reduces progression of early-stage subclinical atherosclerosis (carotid artery intima media thickness) in well-nourished healthy B vitamin “replete” individuals at low risk for cardiovascular disease with a fasting total homocysteine of 9.1 µmol/L or greater.

Source: Stroke, Mar 1, 2009;40:730. Hodis WJ, Dustin L, Mahrer PR, Azen SP, Detrano R, Selhub J, Alaupovic P, Liu C, Liu C, Hwang J, Wilcox AG, Selzer RH. University of Southern California, Keck School of Medicine; University of Southern California, School of Pharmacy; Kaiser Permanente Medical Center, Los Angeles; Harbor–University of California at Los Angeles Medical Center, California; USDA Human Nutrition Research Center on Aging and Department of Vitamin Metabolism and Aging, Tufts University, Boston, Massachusetts; Oklahoma Medical Research Foundation, Oklahoma City; Jet Propulsion Laboratory, California Institute of Technology, Pasadena, California. [E-mail: Howard N. Hodis, MD athero@usc.edu]

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