A Randomized, Double‐Blind, Placebo‐Controlled Study of Oral Vitamin B<sub>12</sub> Supplementation in Older Patients with Subnormal or Borderline Serum Vitamin B<sub>12</sub> Concentrations

Seal, Eric; Metz, J.; Flicker, Leon; Melny, Joy

doi:10.1046/j.1532-5415.2002.50020.x

Cited by 108 publications

(95 citation statements)

References 11 publications

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“…Although a number of studies in healthy populations and in patients have investigated the effect of various doses of folic acid supplementation in lowering tHcy, few have examined the independent effects of vitamin B 12 . In those studies that have administered low-dose vitamin B 12 as a separate treatment, the response of vitamin B 12 biomarkers was the primary outcome and the tHcy response was measured as a secondary objective (21,22) . Furthermore, the study populations were selected for mild vitamin B 12 deficiency and were not pretreated with folic acid before vitamin B 12 supplementation.…”

Section: Vitamin B 12mentioning

confidence: 99%

Homocysteine, B-vitamins and CVD

et al. 2008

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There is considerable interest in plasma homocysteine (tHcy) as a CVD risk factor. Although the secondary prevention trials published to date have been inconclusive in confirming a benefit of tHcy-lowering treatment with B-vitamins on CVD events generally, such studies are widely recognised to have been insufficiently powered to detect a significant effect for the predicted magnitude of association between tHcy and heart disease risk, and therefore cannot be interpreted as evidence that no relationship exists. In fact, a recent meta-analysis of clinical trials has confirmed that folic acid supplementation reduces the risk of stroke, particularly in individuals without a history of stroke. Evidence supporting a causal relationship between elevated tHcy and heart disease also comes from genetic studies. The most important genetic determinant of tHcy in the general population is the common C677T variant in methylenetetrahydrofolate reductase (MTHFR) that results in higher tHcy. Individuals with the homozygous mutant (TT) genotype have a significantly higher (14-21 %) risk of heart disease. Plasma tHcy is very responsive to intervention with the B-vitamins required for its metabolism, in particular folic acid, and to a lesser extent vitamins B 12 and B 6 . Thus, although primarily aimed at reducing neural-tube defects, folic acid fortification may have an important role in the primary prevention of CVD via tHcy lowering. Besides folate, riboflavin is required as a cofactor for MTHFR and enhanced riboflavin status results in a marked lowering in tHcy specifically in individuals with the TT genotype, presumably by neutralising the variant form of the enzyme. About 10 % of the UK and Irish populations have the TT genotype. In the present paper the potential role of folate and related B-vitamins in the primary prevention of CVD and the implications for nutrition policy are explored. B-vitamins: Folate: Homocysteine: CVD Elevated homocysteine as a risk factor for CVDEvidence from numerous prospective and retrospective case-control studies has emerged in recent years to link elevated plasma homocysteine (tHcy) levels with an increased risk of CVD. Meta-analyses of prospective studies have predicted that lowering tHcy by 3 mmol/l (or a reduction of 25% based on an average tHcy of 12 mmol/l) would reduce the risk of heart disease by 11-16 % and stroke by 19-24 % (1,2) . Although none of the secondary prevention trials published in more recent years have been able to confirm the benefit of tHcy-lowering therapy on CVD events generally (3)(4)(5) , it should not be assumed that no relationship exists. It is now generally recognised that these trials lacked sufficient statistical power to detect an effect for the predicted magnitude of association between tHcy and heart disease (6) . In support of this viewpoint, a clear benefit in reducing stroke was shown in one of the previously mentioned 'negative' trials, although this result was not explicit in the conclusions (4) . Moreover, evidence just published from a meta-analysis o...

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Section: Vitamin B 12mentioning

confidence: 99%

Homocysteine, B-vitamins and CVD

et al. 2008

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“…Randomized trials of the effect of lowering tHcy with B-vitamins (folic acid, B12 and, to a lesser extent, B6) on cognitive decline minimize confounding and reverse causality but have produced conflicting or equivocal results. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] The 2 trials that reported a benefit from lowering tHcy did so in subjects with elevated tHcy. 19,27 In view of the uncertainty of the effect of lowering tHcy with B-vitamins on cognition, we aimed to assess, in a prespecified study, whether B-vitamin treatment would reduce the incidence of new cognitive impairment among cognitively unimpaired individuals with recent stroke or transient ischemic attack (TIA) of the brain enrolled in the VITAmins TO Prevent Stroke (VITATOPS) trial, 29,30 and whether the effect of B-vitamins on cognitive function may be augmented in, or limited to, participants with elevated tHcy.…”

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confidence: 99%

Effect of B Vitamins and Lowering Homocysteine on Cognitive Impairment in Patients With Previous Stroke or Transient Ischemic Attack

Hankey

Ford

et al. 2013

Stroke

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Background and Purpose-High plasma total homocysteine (tHcy) has been associated with cognitive impairment but lowering tHcy with B-vitamins has produced equivocal results. We aimed to determine whether B-vitamin supplementation would reduce tHcy and the incidence of new cognitive impairment among individuals with stroke or transient ischemic attack ≥6 months previously. Methods-A total of 8164 patients with stroke or transient ischemic attack were randomly allocated to double-blind treatment with one tablet daily of B-vitamins (folic acid, 2 mg; vitamin B6, 25 mg; vitamin B12, 500 μg) or placebo and followed up for 3.4 years (median) in the VITAmins TO Prevent Stroke (VITATOPS) trial. For this prespecified secondary analysis of VITATOPS, the primary outcome was a new diagnosis of cognitive impairment, defined as a Mini-Mental State Examination (MMSE) score <24 on ≥2 follow-up visits. Secondary outcomes were cognitive decline, and the mean tHcy and MMSE at final follow-up. Results-A total of 3089 participants (38%) voluntarily undertook the MMSE >6 months after the qualifying stroke; 2608 participants were cognitively unimpaired (MMSE ≥24), of whom 2214 participants (1110 B-vitamins versus 1104 placebo) had follow-up MMSEs during 2.8 years (median). At final follow-up, allocation to B-vitamins, compared with placebo, was associated with a reduction in mean tHcy (10.2 μmol/L versus 14.2 μmol/L; P<0.001) but no change from baseline in the mean MMSE score (−0.22 points versus −0.25 points; difference, 0.03; 95% confidence interval, −0.13 to 0.19; P=0.726) and no difference in the incidence of cognitive impairment (5.51% versus 5.47%; risk ratio, 1.01; 95% confidence interval, 0.69-1.48; P=0.976), cognitive decline (9.1% versus 10.3%; risk ratio, 0.89; 0.67-1.18; P=0.414), or cognitive impairment or decline (11.0% versus 11.3%; risk ratio, 0.98; 0.75-1.27; P=0.855). Conclusions-Daily supplementation with folic acid, vitamin B6, and vitamin B12 to a self-selected clinical trial cohort of cognitively unimpaired patients with previous stroke or transient ischemic attack lowered mean tHcy but had no effect on the incidence of cognitive impairment or cognitive decline, as measured by the MMSE, during a median of 2.

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“…With test doses of 10 μg and 50 μg B 12 per day, only the 50 μg dose produced a significant increase in serum B 12 concentration. [13] In another study, 600 μg B 12 /day, 300 times greater than the recommended dietary allowance of 2 μg/day, was needed to normalise low serum B 12 and raised methylmalonic acid. [14] Results in patients with food B 12 malabsorption show similar variation, one study showing increased serum B 12 following a daily dose of 5.9 μg, [15] while in another 250 -1 000 μg/day was required to have any effect.…”

Section: Fff and The Implications For Patients With Vitamin B 12 Defimentioning

confidence: 99%

Haematological implications of folate food fortification

Metz

2013

S Afr Med J

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A Randomized, Double‐Blind, Placebo‐Controlled Study of Oral Vitamin B₁₂ Supplementation in Older Patients with Subnormal or Borderline Serum Vitamin B₁₂ Concentrations

Abstract: Cyanocobalamin supplementation of 50 microg but not 10 microg daily produced a significant increase in serum vitamin B12. This result has implications for the management of patients with subnormal or borderline serum vitamin B12 concentrations and for food fortification with vitamin B12.

Cited by 108 publications

References 11 publications

Homocysteine, B-vitamins and CVD

Homocysteine, B-vitamins and CVD

Effect of B Vitamins and Lowering Homocysteine on Cognitive Impairment in Patients With Previous Stroke or Transient Ischemic Attack

Haematological implications of folate food fortification

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A Randomized, Double‐Blind, Placebo‐Controlled Study of Oral Vitamin B12 Supplementation in Older Patients with Subnormal or Borderline Serum Vitamin B12 Concentrations

Abstract: Cyanocobalamin supplementation of 50 microg but not 10 microg daily produced a significant increase in serum vitamin B12. This result has implications for the management of patients with subnormal or borderline serum vitamin B12 concentrations and for food fortification with vitamin B12.

Cited by 108 publications

References 11 publications

Homocysteine, B-vitamins and CVD

Homocysteine, B-vitamins and CVD

Effect of B Vitamins and Lowering Homocysteine on Cognitive Impairment in Patients With Previous Stroke or Transient Ischemic Attack

Haematological implications of folate food fortification

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A Randomized, Double‐Blind, Placebo‐Controlled Study of Oral Vitamin B₁₂ Supplementation in Older Patients with Subnormal or Borderline Serum Vitamin B₁₂ Concentrations