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Homocysteine Lowering with B Vitamins: Disappointing Results

Despite its homocysteine-lowering effect, high-dose B vitamin supplementation yielded no cardiovascular or cognitive benefit in patients with high-normal homocysteine levels at baseline.

The normal range of blood homocysteine is roughly from 5 to 15 µmol/L; average levels in the U.S. are slightly higher in men than in women, and substantially higher in elderly people than in young adults (Am J Clin Nutr Nov; 84:989). In epidemiologic studies, elevated blood levels are associated with increased cardiovascular risk. Because intake of several B vitamins (particularly folate, B₆, and B₁₂) lowers homocysteine levels, two randomized trials tested the hypothesis that vitamin B supplementation would reduce risk for adverse cardiovascular events.

The HOPE-2 trial involved more than 5500 patients with histories of documented vascular disease or with diabetes plus another risk factor. After 5 years, mean homocysteine levels dropped from 12.2 µmol/L to 9.7 µmol/L in the high-dose B-vitamin group and did not drop significantly in the placebo group. However, no significant difference was found between groups in the primary endpoint of myocardial infarction, stroke, or cardiovascular death (18.8% vs. 19.8%) or in various secondary outcomes (Journal Watch Mar 28 2006).

In a randomized trial of secondary prevention from Norway, 3749 patients with MI during the preceding 7 days received vitamin B supplements or placebo. During an average follow-up of 3 years, supplementation lowered mean homocysteine levels from 13.0 µmol/L to 9.6 µmol/L, but conferred no benefit for any clinical outcome (Journal Watch Mar 28 2006).

Elevated homocysteine levels also have been associated with cognitive decline. In a third randomized trial, New Zealand researchers studied 276 healthy nondemented people (age, 65), with plasma homocysteine levels 13 µmol/L. Although high-dose B-vitamin therapy reduced homocysteine levels by an average of 4.4 µmol/L, after 2 years no benefit on cognition was observed in the B-vitamin group compared with the placebo group (Journal Watch Jun 30 2006).

These three trials convincingly revealed no benefit from high-dose B-vitamin supplementation in selected patient populations with high-normal blood levels of homocysteine, but they say little about the value of B-vitamin supplementation in patients with higher levels (>20 µmol/L) of homocysteine. Folate supplementation of cereals and other foods has reduced the number of such people in many countries, but for the few who remain with high homocysteine levels, B-vitamin supplementation should not be dismissed on the basis of these studies.

— Anthony L. Komaroff, MD

Published in Journal Watch General Medicine December 28, 2006