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(Stroke. 2006;37:547.)
© 2006 American Heart Association, Inc.

Research Reports

Efficacy of B Vitamins in Lowering Homocysteine in Older Men

Maximal Effects for Those With B₁₂ Deficiency and Hyperhomocysteinemia

Leon Flicker, PhD, FRACP; Samuel D. Vasikaran, MD, FRCPA; Jenny Thomas, RN; John M. Acres, Psych; Paul Norman, DS, FRACS; Konrad Jamrozik, DPhil, FAFPHM; Graeme J. Hankey, MD, FRACP Osvaldo P. Almeida, PhD, FRANZCP

From the Department of Core Clinical Pathology and Biochemistry (S.D.V.) and Stroke Unit (G.H.), Royal Perth Hospital, Perth; Schools of Medicine and Pharmacology (L.F., J.T., J.M.A., G.H.), Psychiatry and Clinical Neurosciences (J.M.A., O.P.A.), and Surgery and Pathology (P.N.), University of Western Australia, Perth; School of Population Health (K.J.), University of Queensland, Brisbane, Queensland, Australia.

Correspondence to Leon Flicker, PhD, FRACP, Department of Geriatric Medicine, Royal Perth Hospital, Box X2213 GPO, Perth, Western Australia 6001, Australia. E-mail leonflic{at}cyllene.uwa.edu.au

	Abstract

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Background and Purpose— A higher plasma concentration of total homocysteine (tHcy) is associated with a greater risk of cardiovascular events. Previous studies, largely in younger individuals, have shown that B vitamins lowered tHcy by substantial amounts and that this effect is greater in people with higher tHcy and lower folate levels.

Methods— We undertook a 2-year, double-blind, placebo-controlled, randomized trial in 299 men aged 75 years, comparing treatment with a daily tablet containing 2 mg of folate, 25 mg of B₆, and 400 µg of B₁₂ or placebo. The study groups were balanced regarding age (mean±SD, 78.9±2.8 years), B vitamins, and tHcy at baseline.

Results— Among the 13% with B₁₂ deficiency, the difference in mean changes in treatment and control groups for tHcy was 6.74 µmol/L (95% CI, 3.94 to 9.55 µmol/L) compared with 2.88 µmol/L (95% CI, 0.07 to 5.69 µmol/L) for all others. Among the 20% with hyperhomocysteinaemia, the difference between mean changes in treatment and control groups for men with high plasma tHcy compared with the rest of the group was 2.8 µmol/L (95% CI, 0.6 to 4.9 µmol/L). Baseline vitamin B₁₂, serum folate, and tHcy were significantly associated with changes in plasma tHcy at follow-up (r=0.252, r=0.522, and r=–0.903, respectively; P=0.003, <0.001, and <0.001, respectively) in the vitamin group.

Conclusions— The tHcy-lowering effect of B vitamins was maximal in those who had low B₁₂ or high tHcy levels. Community-dwelling older men, who are likely to be deficient in B₁₂ or have hyperhomocysteinemia, may be most likely to benefit from treatment with B vitamins.

Key Words: aged • clinical trial • homocysteine • vitamins • vitamin B₁₂ deficiency

	Introduction

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High total plasma homocysteine (tHcy) is associated with increased risk of cardiovascular events and dementia. Recent evidence suggests that this association may be causal.¹ A metaanalysis of 12 clinical trials involving 1114 individuals showed that between 0.5 and 5 mg of folic acid daily lowers tHcy by 25% (95% CI, 23% to 28%), with vitamin B₁₂ supplementation (0.02 to 1 mg daily) further reducing tHcy by 7%.² The effect of B-vitamin therapy was more pronounced in people with higher tHcy and lower folate concentrations before treatment. However, the subjects included in this metaanalysis had a mean age of 52 years, most had normal folate and vitamin B₁₂ status, and the mean duration of B-vitamin treatment was only 6 weeks. Because vitamin B₁₂ deficiency is heavily age dependent,³ it is uncertain how effective sustained homocysteine-lowering therapy would be in later life. There is some evidence that, in patients with vascular disease, low B₁₂ levels are not only associated with elevated tHcy but also with carotid plaque area.⁴ Because recent published data suggest that, in the presence of folate repletion, blood concentrations of tHcy are highly dependent on vitamin B₁₂ status,⁵ we hypothesized that the effects of B-vitamin therapy in lowering tHcy may be augmented in populations with a high prevalence of B₁₂ deficiency.

	Methods

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We undertook a double-blind, placebo-controlled, randomized trial of homocysteine-lowering therapy in 299 elderly men aged 75 years, drawn from a population-based trial of screening for abdominal aortic aneurysm.⁶ These men were randomized to treatment with a tablet containing 2 mg of folate plus 25 mg of B₆ and 400 µg of B₁₂ or placebo to be taken once daily with breakfast for 2 years. Measurement of fasting plasma tHcy, serum B₁₂, and folate levels occurred at 6-monthly intervals. Details of recruitment and follow-up are outlined in the Figure. Informed consent was obtained from all of the subjects, and all of the study procedures were approved by the University of Western Australia Institutional Ethics Committee.

View larger version (20K): [in this window] [in a new window]   Flow diagram of recruitment and progress through randomized trial of homocysteine-lowering supplements.

	Results

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Patients in the placebo and vitamin supplement group were evenly matched for age, B vitamin, and tHcy status at baseline (Table). Allocation to B-vitamin supplementation was associated with a significant increase at 6-month follow-up in mean blood concentrations of folate (10.6 nmol/L; 95% CI, 8.8 to 12.4) and vitamin B₁₂ (258 pmol/L; 95% CI, 228 to 288) and a significant reduction in mean tHcy (3.9 µmol/L; 95% CI, 3.1 to 4.6; Table).

View this table: [in this window] [in a new window]   Mean Baseline Values and Absolute Effects on Biochemical Indices in 299 Older Men Given Homocysteine-Lowering Vitamin Supplements

The effect of B-vitamin supplementation on tHcy was augmented among the 38 men (13%) with vitamin B₁₂ deficiency (serum B₁₂ <140 pmol/L) and the 65 men (20%) with hyperhomocysteinaemia (tHcy >15 µmol/L). B-vitamin supplementation reduced mean tHcy by 6.74 µmol/L (95% CI, 3.94 to 9.55 µmol/L) in men with vitamin B₁₂ deficiency (Table). The difference in tHcy between mean changes in treatment and control groups for men with low serum B₁₂ compared with the rest of the group was 2.88 µmol/L (95% CI, 0.07 to 5.69 µmol/L). Using a more liberal definition of relative B₁₂ deficiency of <258 pmol/L, 152 men (55%) were found to be deficient. In comparison to the more severely B₁₂-deficient men, the increase in serum B₁₂ on treatment, when compared with placebo, was greater at 230.8 pmol/L (95% CI, 196.1 to 265.4 pmol/L), but the decrease in tHcy was less at 4.23 µmol/L (95% CI, 3.14 to 5.32 µmol/L).

Among men with hyperhomocysteinaemia, B-vitamin supplementation reduced mean tHcy by 6.63 µmol/L (95% CI, 4.61 to 8.65 µmol/L; Table). The difference between mean changes in treatment and control groups for men with high plasma tHcy compared with the rest of the group was 2.8 µmol/L (95% CI, 0.6 to 4. 9 µmol/L). Only 3 men had a serum folate level below the lower limit of the reference range of 5.5 nmol/L. For those 29 men who had a serum folate in the lowest decile (<13.5 nmol/L), the effect of B-vitamin administration was augmented, with a difference of 6.91 µmol/L (95% CI, 4.05 to 9.77 µmol/L) in tHcy between the 2 groups. In the 150 patients assigned B-vitamin supplements, baseline vitamin B₁₂, serum folate, and tHcy were significantly associated with changes in the concentration of plasma tHcy at follow-up (r=0.25, r=0.52, and r=–0.90, respectively; P=0.003, <0.0001, and <0.0001, respectively).

	Discussion

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These results support the findings of the metaanalysis from the Homocysteine Lowering Trialists’ Collaboration² that the effect of B-vitamin therapy is more pronounced in people with higher tHcy and lower folate concentrations before treatment. In addition, our data indicate that, in an older population with a high prevalence of vitamin B₁₂ deficiency, the effect of B-vitamin therapy was more pronounced in people with lower B₁₂ concentrations before treatment. If ongoing randomized trials show that lowering tHcy does reduce serious vascular events, community-dwelling older men, who are likely to be deficient in B₁₂ and at high absolute risk of vascular events and dementia, may be most likely to benefit.

Summary
Previous studies, largely in younger individuals, have shown that B vitamins lower plasma homocysteine by substantial amounts and that this effect is greater in people with higher homocysteine and lower folate levels. This study confirms this finding in older men, but shows, for the first time, that the homocysteine-lowering effect was maximal in those who had lower B₁₂ levels.

	Acknowledgments

 
This work was supported by grant 139123 from the National Health and Medical Research Council of Australia and an untied research grant from Pfizer CVL. The vitamin and placebo tablets were provided free of charge by Blackmore’s Ltd. These funding sources had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit for publication.

Received October 7, 2005; revision received November 13, 2005; accepted November 16, 2005.

	References

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2. Homocysteine Lowering Trialists’ Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomized trials. BMJ. 1998; 316: 894–898.[Abstract/Free Full Text]

3. Flicker LA, Vasikaran SD, Thomas J, Acres JG, Norman PE, Jamrozik K, Lautenschlager NT, Leedman PJ, Almeida OP. Homocysteine and vitamin status in older people in Perth. Med J Aust. 2004; 180: 539–540.[Medline] [Order article via Infotrieve]

4. Robertson J, Iemolo F, Stabler SP, Allen RH, Spence JD. Vitamin B₁₂, homocysteine and carotid plaque in the era of folic acid fortification of enriched cereal grain products. CMAJ. 2005; 172: 1569–1573.[Abstract/Free Full Text]

5. Quinlivan EP, McPartlin J, McNulty H, Ward M, Strain JJ, Weir DG, Scott JM. Importance of both folic acid and vitamin B₁₂ in reduction of risk of vascular diseases. Lancet. 2002; 359: 227–228.[CrossRef][Medline] [Order article via Infotrieve]

6. Norman PE, Jamrozik K, Lawrence-Brown MM, Le MT, Spencer CA, Tuohy RJ, Parsons RW, Dickinson JA. Population based randomised controlled trial on impact of screening on mortality from abdominal aortic aneurysm. BMJ. 2004; 329: 1259–1262.[Abstract/Free Full Text]

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This Article Abstract Full Text (PDF) All Versions of this Article: 37/2/547    most recent 01.STR.0000198815.07315.68v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Flicker, L. Articles by Almeida, O. P. Search for Related Content PubMed PubMed Citation Articles by Flicker, L. Articles by Almeida, O. P. Related Collections Primary prevention